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Yao X, Ma K, Zhu Y, Cao S. Innate Lymphoid Cells in Inflammatory Bowel Disease. Cells 2025; 14:825. [PMID: 40498001 PMCID: PMC12155180 DOI: 10.3390/cells14110825] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2025] [Revised: 05/22/2025] [Accepted: 05/28/2025] [Indexed: 06/19/2025] Open
Abstract
Inflammatory bowel disease (IBD), including Crohn's disease and ulcerative colitis, is a chronic inflammatory disorder of the gastrointestinal tract with rising incidence and an unclear etiology. Innate lymphoid cells (ILCs) have recently emerged as key regulators of mucosal immunity and tissue homeostasis and are increasingly implicated in IBD. Unlike adaptive lymphocytes, ILCs do not require antigen recognition and clonal expansion to respond rapidly to environmental cues and shape immune responses. In a healthy gut, ILCs maintain intestinal homeostasis by guarding the epithelial barrier, protecting against pathogens, and mounting proper responses to external insults. However, their altered differentiation, proliferation, recruitment, activation, and interaction with other host cells, microbiota, and environmental stimuli may contribute to IBD. In this review, we discuss recent advances in understanding murine and human ILCs in the context of intestinal inflammation and IBD. A deeper understanding of ILC-mediated immune mechanisms may offer novel therapeutic strategies for restoring intestinal homeostasis and improving personalized management of IBD.
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Affiliation(s)
| | | | | | - Siyan Cao
- Division of Gastroenterology, Washington University School of Medicine, St. Louis, MO 63110, USA; (X.Y.); (K.M.); (Y.Z.)
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Askarizadeh F, Butler AE, Kesharwani P, Sahebkar A. Regulatory effect of curcumin on CD40:CD40L interaction and therapeutic implications. Food Chem Toxicol 2025; 200:115369. [PMID: 40043936 DOI: 10.1016/j.fct.2025.115369] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2024] [Revised: 01/24/2025] [Accepted: 03/02/2025] [Indexed: 04/21/2025]
Abstract
Natural compounds have garnered significant attention as potential therapeutic agents due to their inherent properties. Their notable qualities, including safety, efficacy, favorable pharmacokinetic properties, and heightened effectiveness against certain diseases, particularly inflammatory conditions, make them particularly appealing. Among these compounds, curcumin has attracted considerable interest for its unique therapeutic properties and has therefore been extensively studied as a potential therapeutic agent for treating various diseases. Curcumin exhibits diverse anti-inflammatory, antioxidant, and antimicrobial effects. Curcumin's immune system regulatory ability has made it a promising compound for treatment of various inflammatory diseases, such as psoriasis, atherosclerosis, asthma, colitis, IBD, and arthritis. Among the signaling pathways implicated in these conditions, the CD40 receptor together with its ligand, CD40L, are recognized as central players. Studies have demonstrated that the interaction between CD40 and CD40L interaction acts as the primary mediator of the immune response in inflammatory diseases. Numerous studies have explored the impact of curcumin on the CD40:CD40L pathway, highlighting its regulatory effects on this inflammatory pathway and its potential therapeutic use in related inflammatory conditions. In this review, we will consider the evidence concerning curcumin's modulatory effects in inflammatory disease and its potential therapeutic role in regulating the CD40:CD40L pathway.
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Affiliation(s)
- Fatemeh Askarizadeh
- Department of Medical Biotechnology and Nanotechnology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | | | - Prashant Kesharwani
- Department of Pharmaceutics, School of Pharmaceutical Education and Research, Jamia Hamdard, New Delhi, 110062, India.
| | - Amirhossein Sahebkar
- Center for Global Health Research, Saveetha Institute of Medical and Technical Sciences, Saveetha Medical College and Hospitals, Saveetha University, Chennai, India; Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran; Applied Biomedical Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.
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Shah PN, Romar GA, Manukyan A, Ko WC, Hsieh PC, Velasquez GA, Schunkert EM, Fu X, Guleria I, Bronson RT, Wei K, Waldman AH, Vleugels FR, Liang MG, Giobbie-Hurder A, Mostaghimi A, Schmidt BA, Barrera V, Foreman RK, Garber M, Divito SJ. Systemic and skin-limited delayed-type drug hypersensitivity reactions associate with distinct resident and recruited T cell subsets. J Clin Invest 2024; 134:e178253. [PMID: 39042477 PMCID: PMC11364394 DOI: 10.1172/jci178253] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2024] [Accepted: 07/02/2024] [Indexed: 07/25/2024] Open
Abstract
Delayed-type drug hypersensitivity reactions are major causes of morbidity and mortality. The origin, phenotype, and function of pathogenic T cells across the spectrum of severity require investigation. We leveraged recent technical advancements to study skin-resident memory T cells (TRMs) versus recruited T cell subsets in the pathogenesis of severe systemic forms of disease, Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN) and drug reaction with eosinophilia and systemic symptoms (DRESS), and skin-limited disease, morbilliform drug eruption (MDE). Microscopy, bulk transcriptional profiling, and single-cell RNA-sequencing (scRNA-Seq) plus cellular indexing of transcriptomes and epitopes by sequencing (CITE-Seq) plus T cell receptor sequencing (TCR-Seq) supported clonal expansion and recruitment of cytotoxic CD8+ T cells from circulation into skin along with expanded and nonexpanded cytotoxic CD8+ skin TRM in SJS/TEN. Comparatively, MDE displayed a cytotoxic T cell profile in skin without appreciable expansion and recruitment of cytotoxic CD8+ T cells from circulation, implicating TRMs as potential protagonists in skin-limited disease. Mechanistic interrogation in patients unable to recruit T cells from circulation into skin and in a parallel mouse model supported that skin TRMs were sufficient to mediate MDE. Concomitantly, SJS/TEN displayed a reduced Treg signature compared with MDE. DRESS demonstrated recruitment of cytotoxic CD8+ T cells into skin as in SJS/TEN, yet a pro-Treg signature as in MDE. These findings have important implications for fundamental skin immunology and clinical care.
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Affiliation(s)
- Pranali N. Shah
- Department of Dermatology, Brigham and Women’s Hospital (BWH), Harvard Medical School, Boston, Massachusetts, USA
| | - George A. Romar
- Department of Dermatology, Brigham and Women’s Hospital (BWH), Harvard Medical School, Boston, Massachusetts, USA
| | | | - Wei-Che Ko
- Bioinformatics and Integrative Biology Program, and
- Department of Dermatology, University of Massachusetts Medical School, Worcester, Massachusetts, USA
| | - Pei-Chen Hsieh
- Department of Dermatology, Brigham and Women’s Hospital (BWH), Harvard Medical School, Boston, Massachusetts, USA
| | - Gustavo A. Velasquez
- Department of Dermatology, Brigham and Women’s Hospital (BWH), Harvard Medical School, Boston, Massachusetts, USA
| | - Elisa M. Schunkert
- Department of Dermatology, Brigham and Women’s Hospital (BWH), Harvard Medical School, Boston, Massachusetts, USA
| | - Xiaopeng Fu
- Department of Dermatology, Brigham and Women’s Hospital (BWH), Harvard Medical School, Boston, Massachusetts, USA
| | - Indira Guleria
- Department of Pathology, BWH, Harvard Medical School, Boston, Massachusetts, USA
- Department of Pathology, Beth Israel Deaconess Medical Center, and
| | - Roderick T. Bronson
- Department of Microbiology and Immunobiology, Harvard Medical School, Boston, Massachusetts, USA
| | - Kevin Wei
- Division of Rheumatology, Inflammation, and Immunity, BWH and Harvard Medical School, Boston, Massachusetts, USA
| | - Abigail H. Waldman
- Department of Dermatology, Brigham and Women’s Hospital (BWH), Harvard Medical School, Boston, Massachusetts, USA
| | - Frank R. Vleugels
- Department of Dermatology, Brigham and Women’s Hospital (BWH), Harvard Medical School, Boston, Massachusetts, USA
| | - Marilyn G. Liang
- Department of Dermatology, Boston Children’s Hospital (BCH), Harvard Medical School, Boston, Massachusetts, USA
| | - Anita Giobbie-Hurder
- Department of Data Science, Dana Farber Cancer Institute, Boston, Massachusetts, USA
| | - Arash Mostaghimi
- Department of Dermatology, Brigham and Women’s Hospital (BWH), Harvard Medical School, Boston, Massachusetts, USA
| | | | - Victor Barrera
- Bioinformatics Core, Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA
| | - Ruth K. Foreman
- Department of Pathology, Massachusetts General Hospital, Boston, Massachusetts, USA
| | - Manuel Garber
- Bioinformatics Core
- Bioinformatics and Integrative Biology Program, and
- Department of Dermatology, University of Massachusetts Medical School, Worcester, Massachusetts, USA
| | - Sherrie J. Divito
- Department of Dermatology, Brigham and Women’s Hospital (BWH), Harvard Medical School, Boston, Massachusetts, USA
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Gao X, Tang Y, Kong L, Fan Y, Wang C, Wang R. Treg cell: Critical role of regulatory T-cells in depression. Pharmacol Res 2023; 195:106893. [PMID: 37611836 DOI: 10.1016/j.phrs.2023.106893] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/23/2023] [Revised: 07/28/2023] [Accepted: 08/17/2023] [Indexed: 08/25/2023]
Abstract
Depression is a highly prevalent disorder of the central nervous system. The neuropsychiatric symptoms of clinical depression are persistent and include fatigue, anorexia, weight loss, altered sleep patterns, hyperalgesia, melancholia, anxiety, and impaired social behaviours. Mounting evidences suggest that neuroinflammation triggers dysregulated cellular immunity and increases susceptibility to psychiatric diseases. Neuroimmune responses have transformed the clinical approach to depression because of their roles in its pathophysiology and their therapeutic potential. In particular, activated regulatory T (Treg) cells play an increasingly evident role in the inflammatory immune response. In this review, we summarized the available data and discussed in depth the fundamental roles of Tregs in the pathogenesis of depression, as well as the clinical therapeutic potential of Tregs. We aimed to provide recent information regarding the potential of Tregs as immune-modulating biologics for the treatment and prevention of long-term neuropsychiatric symptoms of depression.
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Affiliation(s)
- Xiao Gao
- Department of Geriatrics, Qingdao Mental Health Center, 26600 Qingdao, Shandong Province, China
| | - Yuru Tang
- Department of Critical Care Medicine, The Affiliated Hospital of Qingdao University, 26600 Qingdao, Shandong Province, China
| | - Lingli Kong
- Department of Geriatrics, Qingdao Mental Health Center, 26600 Qingdao, Shandong Province, China
| | - Yong Fan
- Department of Geriatrics, Qingdao Mental Health Center, 26600 Qingdao, Shandong Province, China
| | - Chunxia Wang
- Department of Geriatrics, Qingdao Mental Health Center, 26600 Qingdao, Shandong Province, China.
| | - Rui Wang
- Department of Pain Management, Qingdao Hospital, University of Health and Rehabilitation Sciences (Qingdao Municipal Hospital), 26600 Qingdao, Shandong Province, China.
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Wang Z, Ou Q, Gao L. The increased cfRNA of TNFSF4 in peripheral blood at late gestation and preterm labor: its implication as a noninvasive biomarker for premature delivery. Front Immunol 2023; 14:1154025. [PMID: 37275889 PMCID: PMC10232964 DOI: 10.3389/fimmu.2023.1154025] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2023] [Accepted: 04/27/2023] [Indexed: 06/07/2023] Open
Abstract
INTRODUCTION Given the important roles of immune tolerance and inflammation in both preterm and term labor, some inflammation-related genes could be related to the initiation of labor, even preterm labor. Inspection of cell-free RNA (cfRNA) engaged in inflammation in maternal blood may represent the varied gestational age and may have significant implications for the development of noninvasive diagnostics for preterm birth. METHODS To identify potential biomarkers of preterm birth, we investigated the cfRNA and exosomal miRNA in the peripheral blood of pregnant women at different gestational ages that undergo term labor or preterm labor. 17 inflammatory initiation-related cfRNAs were screened by overlapping with the targets of decreasing miRNAs during gestation and highly expressed cfRNAs at late gestation in maternal blood. To reveal the origins and mechanisms of these screened cfRNAs, the datasets of single-cell RNA sequencing from peripheral blood mononuclear cells of pregnant women, the fetal lung, and the placenta across different gestational ages were analyzed. RESULTS During late gestation, TNFSF4 expression increased exclusively in pro-inflammatory macrophages of maternal blood, whereas its receptor, TNFRSF4, increased expression in T cells from the decidua, which suggested the potential cell-cell communication of maternally-originated pro-inflammatory macrophages with the decidual T cells and contributed to the initiation of labor. Additionally, the cfRNA of TNFSF4 was also increased in preterm labor compared to term labor in the validation cohorts. The EIF2AK2 and TLR4 transcripts were increased in pro-inflammatory macrophages from both fetal lung and placenta but not in those from maternal mononuclear cells at late gestation, suggesting these cfRNAs are possibly derived from fetal tissues exclusively. Moreover, EIF2AK2 and TLR4 transcripts were found highly expressed in the pro-inflammatory macrophages from decidua as well, which suggested these specific fetal-origin macrophages may function at the maternal-fetal interface to stimulate uterine contractions, which have been implicated as the trigger of parturition and preterm labor. DISCUSSION Taken together, our findings not only revealed the potential of peripheral TNFSF4 as a novel cfRNA biomarker for noninvasive testing of preterm labor but further illustrated how maternal and fetal signals coordinately modulate the inflammatory process at the maternal-fetal interface, causing the initiation of term or preterm labor.
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Affiliation(s)
- Zhe Wang
- Department of Physiology, College of Basic Medical Sciences, Naval Medical University, Shanghai, China
| | - Qingjian Ou
- Department of Ophthalmology of Tongji Hospital, School of Medicine, Tongji University, Shanghai, China
| | - Lu Gao
- Department of Physiology, College of Basic Medical Sciences, Naval Medical University, Shanghai, China
- Shanghai Key Laboratory for Assisted Reproduction and Reproductive Genetics, Shanghai Jiaotong University, Shanghai, China
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Iriki H, Takahashi H, Amagai M. Diverse Role of OX40 on T Cells as a Therapeutic Target for Skin Diseases. J Invest Dermatol 2023; 143:545-553. [PMID: 36842860 DOI: 10.1016/j.jid.2022.11.009] [Citation(s) in RCA: 15] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2022] [Revised: 11/22/2022] [Accepted: 11/24/2022] [Indexed: 02/26/2023]
Abstract
OX40 is an important costimulatory molecule for T-cell expansion and survival. Because OX40 is expressed on most T-cell subsets, it is an attractive therapeutic target for a variety of T-cell‒mediated diseases. Clinical trials are already underway for some skin inflammatory diseases. In this review, we present various observations that improve our understanding of how OX40-targeted therapy can be applied for skin inflammatory diseases, such as atopic dermatitis and psoriasis, T helper (Th)2- and Th17-mediated diseases, respectively. The important OX40/OX40L-mediated interaction between T cells and other immune cells is also discussed in terms of skin autoimmune diseases, such as alopecia areata and pemphigus. Regulatory T cells (Tregs) highly express OX40, and the skin harbors a large Treg population; thus, understanding how OX40-targeted treatment acts on Tregs is vital for the development of therapeutic strategies for various skin diseases.
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Affiliation(s)
- Hisato Iriki
- Department of Dermatology, Keio University School of Medicine, Tokyo, Japan
| | - Hayato Takahashi
- Department of Dermatology, Keio University School of Medicine, Tokyo, Japan
| | - Masayuki Amagai
- Department of Dermatology, Keio University School of Medicine, Tokyo, Japan; Laboratory for Skin Homeostasis, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan.
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Voskens C, Stoica D, Rosenberg M, Vitali F, Zundler S, Ganslmayer M, Knott H, Wiesinger M, Wunder J, Kummer M, Siegmund B, Schnoy E, Rath T, Hartmann A, Hackstein H, Schuler-Thurner B, Berking C, Schuler G, Atreya R, Neurath MF. Autologous regulatory T-cell transfer in refractory ulcerative colitis with concomitant primary sclerosing cholangitis. Gut 2023; 72:49-53. [PMID: 35428657 PMCID: PMC9763232 DOI: 10.1136/gutjnl-2022-327075] [Citation(s) in RCA: 46] [Impact Index Per Article: 23.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/01/2022] [Accepted: 03/17/2022] [Indexed: 02/04/2023]
Abstract
OBJECTIVE Ulcerative colitis (UC) is a chronic, debilitating immune-mediated disease driven by disturbed mucosal homeostasis, with an excess of intestinal effector T cells and an insufficient expansion of mucosal regulatory T cells (Tregs). We here report on the successful adoptive transfer of autologous, ex vivo expanded Tregs in a patient with refractory UC and associated primary sclerosing cholangitis (PSC), for which effective therapy is currently not available. DESIGN The patient received a single infusion of 1×106 autologous, ex vivo expanded, polyclonal Tregs per kilogram of body weight, and the clinical, biochemical, endoscopic and histological responses were assessed 4 and 12 weeks after adoptive Treg transfer. RESULTS The patient showed clinical, biochemical, endoscopic and histological signs of response until week 12 after adoptive Treg transfer, which was associated with an enrichment of intestinal CD3+/FoxP3+ and CD3+/IL-10+ T cells and increased mucosal transforming growth factor beta and amphiregulin levels. Moreover, there was marked improvement of PSC with reduction of liver enzymes. This pronounced effect lasted for 4 weeks before values started to increase again. CONCLUSION These findings suggest that adoptive Treg therapy might be effective in refractory UC and might open new avenues for clinical trials in PSC. TRIAL REGISTRATION NUMBER NCT04691232.
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Affiliation(s)
- Caroline Voskens
- Department of Dermatology, Erlangen University Hospital, Erlangen, Germany
- Deutsches Zentrum für Immuntherapie (DZI), Erlangen, Germany
| | - Diane Stoica
- Department of Dermatology, Erlangen University Hospital, Erlangen, Germany
- Deutsches Zentrum für Immuntherapie (DZI), Erlangen, Germany
| | - Marita Rosenberg
- Department of Dermatology, Erlangen University Hospital, Erlangen, Germany
- Deutsches Zentrum für Immuntherapie (DZI), Erlangen, Germany
| | - Francesco Vitali
- Deutsches Zentrum für Immuntherapie (DZI), Erlangen, Germany
- Department of Medicine 1, Gastroenterology, Endocrinology and Pneumology, Erlangen University Hospital, Erlangen, Germany
| | - Sebastian Zundler
- Deutsches Zentrum für Immuntherapie (DZI), Erlangen, Germany
- Department of Medicine 1, Gastroenterology, Endocrinology and Pneumology, Erlangen University Hospital, Erlangen, Germany
| | - Marion Ganslmayer
- Deutsches Zentrum für Immuntherapie (DZI), Erlangen, Germany
- Department of Medicine 1, Gastroenterology, Endocrinology and Pneumology, Erlangen University Hospital, Erlangen, Germany
| | - Heike Knott
- Deutsches Zentrum für Immuntherapie (DZI), Erlangen, Germany
- Department of Medicine 1, Gastroenterology, Endocrinology and Pneumology, Erlangen University Hospital, Erlangen, Germany
| | - Manuel Wiesinger
- Department of Dermatology, Erlangen University Hospital, Erlangen, Germany
- Deutsches Zentrum für Immuntherapie (DZI), Erlangen, Germany
| | - Jutta Wunder
- Deutsches Zentrum für Immuntherapie (DZI), Erlangen, Germany
- Department of Medicine 1, Gastroenterology, Endocrinology and Pneumology, Erlangen University Hospital, Erlangen, Germany
| | - Mirko Kummer
- Department of Dermatology, Erlangen University Hospital, Erlangen, Germany
- Deutsches Zentrum für Immuntherapie (DZI), Erlangen, Germany
| | - Britta Siegmund
- Medical Department, Division of Gastroenterology, Infectious Diseases and Rheumatology, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Campus Benjamin Franklin, Berlin, Germany
| | - Elisabeth Schnoy
- Department of Gastroenterology, University Hospital Augsburg, Augsburg, Germany
| | - Timo Rath
- Deutsches Zentrum für Immuntherapie (DZI), Erlangen, Germany
- Department of Medicine 1, Gastroenterology, Endocrinology and Pneumology, Erlangen University Hospital, Erlangen, Germany
| | - Arndt Hartmann
- Institute of Pathology, Erlangen University Hospital, Erlangen, Germany
| | - Holger Hackstein
- Department of Transfusion Medicine, Erlangen University Hospital, Erlangen, Germany
| | - Beatrice Schuler-Thurner
- Department of Dermatology, Erlangen University Hospital, Erlangen, Germany
- Deutsches Zentrum für Immuntherapie (DZI), Erlangen, Germany
| | - Carola Berking
- Department of Dermatology, Erlangen University Hospital, Erlangen, Germany
- Deutsches Zentrum für Immuntherapie (DZI), Erlangen, Germany
| | - Gerold Schuler
- Department of Dermatology, Erlangen University Hospital, Erlangen, Germany
- Deutsches Zentrum für Immuntherapie (DZI), Erlangen, Germany
| | - Raja Atreya
- Deutsches Zentrum für Immuntherapie (DZI), Erlangen, Germany
- Department of Medicine 1, Gastroenterology, Endocrinology and Pneumology, Erlangen University Hospital, Erlangen, Germany
| | - Markus F Neurath
- Deutsches Zentrum für Immuntherapie (DZI), Erlangen, Germany
- Department of Medicine 1, Gastroenterology, Endocrinology and Pneumology, Erlangen University Hospital, Erlangen, Germany
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Abdeladhim M, Karnell JL, Rieder SA. In or out of control: Modulating regulatory T cell homeostasis and function with immune checkpoint pathways. Front Immunol 2022; 13:1033705. [PMID: 36591244 PMCID: PMC9799097 DOI: 10.3389/fimmu.2022.1033705] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2022] [Accepted: 11/16/2022] [Indexed: 12/16/2022] Open
Abstract
Regulatory T cells (Tregs) are the master regulators of immunity and they have been implicated in different disease states such as infection, autoimmunity and cancer. Since their discovery, many studies have focused on understanding Treg development, differentiation, and function. While there are many players in the generation and function of truly suppressive Tregs, the role of checkpoint pathways in these processes have been studied extensively. In this paper, we systematically review the role of different checkpoint pathways in Treg homeostasis and function. We describe how co-stimulatory and co-inhibitory pathways modulate Treg homeostasis and function and highlight data from mouse and human studies. Multiple checkpoint pathways are being targeted in cancer and autoimmunity; therefore, we share insights from the clinic and discuss the effect of experimental and approved therapeutics on Treg biology.
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Webb ER, Moreno-Vincente J, Easton A, Lanati S, Taylor M, James S, Williams EL, English V, Penfold C, Beers SA, Gray JC. Cyclophosphamide depletes tumor infiltrating T regulatory cells and combined with anti-PD-1 therapy improves survival in murine neuroblastoma. iScience 2022; 25:104995. [PMID: 36097618 PMCID: PMC9463572 DOI: 10.1016/j.isci.2022.104995] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2021] [Revised: 05/20/2022] [Accepted: 08/18/2022] [Indexed: 10/27/2022] Open
Abstract
The outcome for children with high-risk neuroblastoma is poor despite intensive multi-modal treatment protocols. Toxicity from current treatments is significant, and novel approaches are needed to improve outcome. Cyclophosphamide (CPM) is a key component of current chemotherapy regimens and is known to have immunomodulatory effects. However, this has not been investigated in the context of tumor infiltrating lymphocytes in neuroblastoma. Using murine models of neuroblastoma, the immunomodulatory effects of low-dose CPM were investigated using detailed immunophenotyping. We demonstrated that CPM resulted in a specific depletion of intratumoral T regulatory cells by apoptosis, and when combined with anti-PD-1 antibody therapy, this resulted in improved therapeutic efficacy. CPM combined with anti-PD-1 therapy was demonstrated to be an effective combinational therapy, with metronomic CPM found to be more effective than single dosing in more resistant tumor models. Overall, this pre-clinical data strongly support clinical evaluation of such combination strategies in neuroblastoma.
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Affiliation(s)
- Emily R. Webb
- Antibody and Vaccine Group, Centre for Cancer Immunology, University of Southampton Faculty of Medicine, Tremona Road, Southampton, Hampshire SO16 6YD, UK
| | - Julia Moreno-Vincente
- Antibody and Vaccine Group, Centre for Cancer Immunology, University of Southampton Faculty of Medicine, Tremona Road, Southampton, Hampshire SO16 6YD, UK
| | - Alistair Easton
- Antibody and Vaccine Group, Centre for Cancer Immunology, University of Southampton Faculty of Medicine, Tremona Road, Southampton, Hampshire SO16 6YD, UK
- Cellular Pathology, University Hospitals Southampton NHS Foundation Trust, Southampton SO16 6YD, UK
| | - Silvia Lanati
- Antibody and Vaccine Group, Centre for Cancer Immunology, University of Southampton Faculty of Medicine, Tremona Road, Southampton, Hampshire SO16 6YD, UK
| | - Martin Taylor
- Antibody and Vaccine Group, Centre for Cancer Immunology, University of Southampton Faculty of Medicine, Tremona Road, Southampton, Hampshire SO16 6YD, UK
| | - Sonya James
- Antibody and Vaccine Group, Centre for Cancer Immunology, University of Southampton Faculty of Medicine, Tremona Road, Southampton, Hampshire SO16 6YD, UK
| | - Emily L. Williams
- Antibody and Vaccine Group, Centre for Cancer Immunology, University of Southampton Faculty of Medicine, Tremona Road, Southampton, Hampshire SO16 6YD, UK
| | - Vikki English
- Antibody and Vaccine Group, Centre for Cancer Immunology, University of Southampton Faculty of Medicine, Tremona Road, Southampton, Hampshire SO16 6YD, UK
| | - Chris Penfold
- Antibody and Vaccine Group, Centre for Cancer Immunology, University of Southampton Faculty of Medicine, Tremona Road, Southampton, Hampshire SO16 6YD, UK
| | - Stephen A. Beers
- Antibody and Vaccine Group, Centre for Cancer Immunology, University of Southampton Faculty of Medicine, Tremona Road, Southampton, Hampshire SO16 6YD, UK
| | - Juliet C. Gray
- Antibody and Vaccine Group, Centre for Cancer Immunology, University of Southampton Faculty of Medicine, Tremona Road, Southampton, Hampshire SO16 6YD, UK
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Choi J, Kim BR, Akuzum B, Chang L, Lee JY, Kwon HK. TREGking From Gut to Brain: The Control of Regulatory T Cells Along the Gut-Brain Axis. Front Immunol 2022; 13:916066. [PMID: 35844606 PMCID: PMC9279871 DOI: 10.3389/fimmu.2022.916066] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2022] [Accepted: 05/30/2022] [Indexed: 12/12/2022] Open
Abstract
The human gastrointestinal tract has an enormous and diverse microbial community, termed microbiota, that is necessary for the development of the immune system and tissue homeostasis. In contrast, microbial dysbiosis is associated with various inflammatory and autoimmune diseases as well as neurological disorders in humans by affecting not only the immune system in the gastrointestinal tract but also other distal organs. FOXP3+ regulatory T cells (Tregs) are a subset of CD4+ helper T cell lineages that function as a gatekeeper for immune activation and are essential for peripheral autoimmunity prevention. Tregs are crucial to the maintenance of immunological homeostasis and tolerance at barrier regions. Tregs reside in both lymphoid and non-lymphoid tissues, and tissue-resident Tregs have unique tissue-specific phenotype and distinct function. The gut microbiota has an impact on Tregs development, accumulation, and function in periphery. Tregs, in turn, modulate antigen-specific responses aimed towards gut microbes, which supports the host–microbiota symbiotic interaction in the gut. Recent studies have indicated that Tregs interact with a variety of resident cells in central nervous system (CNS) to limit the progression of neurological illnesses such as ischemic stroke, Alzheimer’s disease, and Parkinson’s disease. The gastrointestinal tract and CNS are functionally connected, and current findings provide insights that Tregs function along the gut-brain axis by interacting with immune, epithelial, and neuronal cells. The purpose of this study is to explain our current knowledge of the biological role of tissue-resident Tregs, as well as the interaction along the gut-brain axis.
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Affiliation(s)
- Juli Choi
- Department of Microbiology and Immunology, Yonsei University College of Medicine, Seoul, South Korea
- Institute for Immunology and Immunological Diseases, Yonsei University College of Medicine, Seoul, South Korea
| | - Bo-Ram Kim
- Department of Microbiology and Immunology, Yonsei University College of Medicine, Seoul, South Korea
| | - Begum Akuzum
- Department of Microbiology and Immunology, Yonsei University College of Medicine, Seoul, South Korea
| | - Leechung Chang
- Department of Microbiology and Immunology, Yonsei University College of Medicine, Seoul, South Korea
- Institute for Immunology and Immunological Diseases, Yonsei University College of Medicine, Seoul, South Korea
| | - June-Yong Lee
- Department of Microbiology and Immunology, Yonsei University College of Medicine, Seoul, South Korea
- Institute for Immunology and Immunological Diseases, Yonsei University College of Medicine, Seoul, South Korea
- Brain Korea 21 PLUS Project for Medical Sciences, Yonsei University College of Medicine, Seoul, South Korea
- *Correspondence: June-Yong Lee, ; Ho-Keun Kwon,
| | - Ho-Keun Kwon
- Department of Microbiology and Immunology, Yonsei University College of Medicine, Seoul, South Korea
- Institute for Immunology and Immunological Diseases, Yonsei University College of Medicine, Seoul, South Korea
- Brain Korea 21 PLUS Project for Medical Sciences, Yonsei University College of Medicine, Seoul, South Korea
- *Correspondence: June-Yong Lee, ; Ho-Keun Kwon,
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11
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Copsel SN, Wolf D, Pfeiffer B, Barreras H, Perez VL, Levy RB. Recipient Tregs: Can They Be Exploited for Successful Hematopoietic Stem Cell Transplant Outcomes? Front Immunol 2022; 13:932527. [PMID: 35799783 PMCID: PMC9253768 DOI: 10.3389/fimmu.2022.932527] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2022] [Accepted: 05/18/2022] [Indexed: 02/03/2023] Open
Abstract
Human and mouse CD4+FoxP3+ T cells (Tregs) comprise non-redundant regulatory compartments which maintain self-tolerance and have been found to be of potential therapeutic usefulness in autoimmune disorders and transplants including allogeneic hematopoietic stem cell transplantation (allo-HSCT). There is substantial literature interrogating the application of donor derived Tregs for the prevention of graft versus host disease (GVHD). This Mini-Review will focus on the recipient's Tregs which persist post-transplant. Although treatment in patients with low dose IL-2 months post-HSCT are encouraging, manipulating Tregs in recipients early post-transplant is challenging, in part likely an indirect consequence of damage to the microenvironment required to support Treg expansion of which little is understood. This review will discuss the potential for manipulating recipient Tregs in vivo prior to and after HSCT (fusion proteins, mAbs). Strategies that would circumvent donor/recipient peripheral blood harvest, cell culture and ex-vivo Treg expansion will be considered for the translational application of Tregs to improve HSCT outcomes.
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Affiliation(s)
- Sabrina N. Copsel
- Department of Microbiology and Immunology, University of Miami School of Medicine, Miami, FL, United States
| | - Dietlinde Wolf
- Sylvester Comprehensive Cancer Center, University of Miami School of Medicine, Miami, FL, United States
| | - Brent Pfeiffer
- Department of Pediatrics, University of Miami School of Medicine, Miami, FL, United States
| | - Henry Barreras
- Department of Microbiology and Immunology, University of Miami School of Medicine, Miami, FL, United States
| | - Victor L. Perez
- Foster Center for Ocular Immunology, Duke Eye Center, Duke University, Durham, NC, United States
| | - Robert B. Levy
- Department of Microbiology and Immunology, University of Miami School of Medicine, Miami, FL, United States,Sylvester Comprehensive Cancer Center, University of Miami School of Medicine, Miami, FL, United States,Department of Ophthalmology, University of Miami School of Medicine, Miami, FL, United States,*Correspondence: Robert B. Levy,
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12
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Combination of OX40 Co-Stimulation, Radiotherapy, and PD-1 Inhibition in a Syngeneic Murine Triple-Negative Breast Cancer Model. Cancers (Basel) 2022; 14:cancers14112692. [PMID: 35681672 PMCID: PMC9179485 DOI: 10.3390/cancers14112692] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2022] [Revised: 05/20/2022] [Accepted: 05/27/2022] [Indexed: 12/10/2022] Open
Abstract
Simple Summary This experimental study was designed in order to investigate the efficacy of the triple combination of radiation (SBRT), PD-1 blockade, and OX40 co-stimulation in a syngeneic murine model using ‘immunologically cold’ triple-negative breast cancer cells. SBRT can induce immunogenic tumor cell deaths and act as an in situ vaccine while OX40 signaling has been shown to improve anticancer immunity combined with PD-1 inhibition via multiple preclinical studies. In our study, triple combination therapy significantly improved primary/abscopal tumor control and reduced lung metastases compared to single or dual therapies. This was found to be through an increased ratio of CD8+ T cells to regulatory T cells and a reduced proportion of exhausted T cells in the tumor microenvironment. Abstract Immune checkpoint inhibitors have been successful in a wide range of tumor types but still have limited efficacy in immunologically cold tumors, such as breast cancers. We hypothesized that the combination of agonistic anti-OX40 (α-OX40) co-stimulation, PD-1 blockade, and radiotherapy would improve the therapeutic efficacy of the immune checkpoint blockade in a syngeneic murine triple-negative breast cancer model. Murine triple-negative breast cancer cells (4T1) were grown in immune-competent BALB/c mice, and tumors were irradiated with 24 Gy in three fractions. PD-1 blockade and α-OX40 were administered five times every other day. Flow cytometric analyses and immunohistochemistry were used to monitor subsequent changes in the immune cell repertoire. The combination of α-OX40, radiotherapy, and PD-1 blockade significantly improved primary tumor control, abscopal effects, and long-term survival beyond 2 months (60%). In the tumor microenvironment, the ratio of CD8+ T cells to CD4 + FOXP3+ regulatory T cells was significantly elevated and exhausted CD8+ T cells (PD-1+, CTLA-4+, TIM-3+, or LAG-3+ cells) were significantly reduced in the triple combination group. Systemically, α-OX40 co-stimulation and radiation significantly increased the CD103+ dendritic cell response in the spleen and plasma IFN-γ, respectively. Together, our results suggest that the combination of α-OX40 co-stimulation and radiation is a viable approach to overcome therapeutic resistance to PD-1 blockade in immunologically cold tumors, such as triple-negative breast cancer.
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13
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Krovi SH, Kuchroo VK. Activation pathways that drive CD4 + T cells to break tolerance in autoimmune diseases . Immunol Rev 2022;307:161-190. [PMID: 35142369 PMCID: PMC9255211 DOI: 10.1111/imr.13071] [Citation(s) in RCA: 26] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2022] [Accepted: 01/22/2022] [Indexed: 12/11/2022]
Abstract
Autoimmune diseases are characterized by dysfunctional immune systems that misrecognize self as non-self and cause tissue destruction. Several cell types have been implicated in triggering and sustaining disease. Due to a strong association of major histocompatibility complex II (MHC-II) proteins with various autoimmune diseases, CD4+ T lymphocytes have been thoroughly investigated for their roles in dictating disease course. CD4+ T cell activation is a coordinated process that requires three distinct signals: Signal 1, which is mediated by antigen recognition on MHC-II molecules; Signal 2, which boosts signal 1 in a costimulatory manner; and Signal 3, which helps to differentiate the activated cells into functionally relevant subsets. These signals are disrupted during autoimmunity and prompt CD4+ T cells to break tolerance. Herein, we review our current understanding of how each of the three signals plays a role in three different autoimmune diseases and highlight the genetic polymorphisms that predispose individuals to autoimmunity. We also discuss the drawbacks of existing therapies and how they can be addressed to achieve lasting tolerance in patients.
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Affiliation(s)
- Sai Harsha Krovi
- Evergrande Center for Immunologic Diseases, Harvard Medical School and Brigham and Women's Hospital, Boston, Massachusetts, USA
- Klarman Cell Observatory, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA
| | - Vijay K Kuchroo
- Evergrande Center for Immunologic Diseases, Harvard Medical School and Brigham and Women's Hospital, Boston, Massachusetts, USA
- Klarman Cell Observatory, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA
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14
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Chen P, Wang H, Zhao L, Guo H, Zhang L, Zhang W, Sun C, Zhao S, Li W, Zhu J, Yu J, Wu C, He Y. Immune Checkpoints OX40 and OX40L in Small-Cell Lung Cancer: Predict Prognosis and Modulate Immune Microenvironment. Front Oncol 2021; 11:713853. [PMID: 34900670 PMCID: PMC8652148 DOI: 10.3389/fonc.2021.713853] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2021] [Accepted: 08/04/2021] [Indexed: 12/24/2022] Open
Abstract
Background OX40 and OX40 ligand (OX40L), as essential immune checkpoint (IC) modulators, are highly correlated with cancer immunity regulation as well as tumor microenvironment (TME). Immunotherapy showed outstanding advantages in small-cell lung cancer (SCLC) therapy. However, functions and clinical significance of OX40 and OX40L in SCLC were not clear yet. Materials and Methods SCLC samples of 143 patients were collected for immunohistochemistry (IHC) or whole-exome sequencing (WES). We comprehensively explored the expression and mutation of OX40/OX40L in SCLC, and systematically linked OX40/OX40L with TME. Results The expression of OX40/OX40L on tumor cells and tumor-infiltrating lymphocytes (TILs) was found in the IHC cohort and verified in other cohorts with SCLC tissues and cell lines. The results showed co-expression patterns among OX40/OX40L, other ICs, and T-cell markers. The WES data suggested that OX40/OX40L mutation is rare in SCLC (<5%). Patients with positive OX40 protein expression on TILs showed substantially higher recurrence-free survival than those with negative expression (p=0.009). The external dataset also indicated that high OX40/OX40L expression was correlated with better prognosis [overall survival: OX40, p<0.001; OX40L, p=0.019]. Importantly, activation of immunity and high infiltration of CD4(+) and CD8(+) T cells were observed in the high OX40/OX40L expression group. Conclusions Collectively, this work highlighted the significance of OX40 and OX40L in prognosis and TME cell infiltration characterization of SCLC. Evaluating the OX40/OX40L-expression levels of individual patients with SCLC might contribute to guiding more precise therapy.
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Affiliation(s)
- Peixin Chen
- School of Medicine, Tongji University, Shanghai, China.,Department of Medical Oncology, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai, China
| | - Hao Wang
- School of Medicine, Tongji University, Shanghai, China.,Department of Medical Oncology, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai, China
| | - Lishu Zhao
- School of Medicine, Tongji University, Shanghai, China.,Department of Medical Oncology, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai, China
| | - Haoyue Guo
- School of Medicine, Tongji University, Shanghai, China.,Department of Medical Oncology, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai, China
| | - Liping Zhang
- Department of Pathology, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, China
| | - Wei Zhang
- Department of Pathology, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, China
| | - Chenglong Sun
- School of Medicine, Tongji University, Shanghai, China.,Anhui No. 2 Provincial People's Hospital, Hefei, China
| | - Sha Zhao
- School of Medicine, Tongji University, Shanghai, China.,Department of Medical Oncology, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai, China
| | - Wei Li
- School of Medicine, Tongji University, Shanghai, China.,Department of Medical Oncology, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai, China
| | - Jun Zhu
- School of Medicine, Tongji University, Shanghai, China.,Department of Medical Oncology, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai, China
| | - Jia Yu
- School of Medicine, Tongji University, Shanghai, China.,Department of Medical Oncology, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai, China
| | - Chunyan Wu
- Department of Pathology, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, China
| | - Yayi He
- School of Medicine, Tongji University, Shanghai, China.,Department of Medical Oncology, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai, China
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15
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Peripheral tolerance by Treg via constraining OX40 signal in autoreactive T cells against desmoglein 3, a target antigen in pemphigus. Proc Natl Acad Sci U S A 2021; 118:2026763118. [PMID: 34848535 PMCID: PMC8670434 DOI: 10.1073/pnas.2026763118] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/13/2021] [Indexed: 12/16/2022] Open
Abstract
Immune tolerance is crucial to prevent harmful immune reactions against self-antigens and well operated by central thymic tolerance and peripheral tissue tolerance. However, peripheral tolerance had been investigated under influence from thymic tolerance. We successfully decoupled peripheral tolerance from thymic tolerance by utilizing autoantigen-deficient thymus. Experiments revealed that self-antigen presentation in steady state initiated proliferation but subsequent disappearance of autoreactive CD4+ T cells in draining lymph nodes. After screening of representative candidates, including Ctla4, autoimmune regulator, and Pd-1, the mechanism was found to depend on regulatory T cell (Treg) function that constrained OX40 signaling of the T cells. This study presented fundamental, but potent, Treg-mediated tolerance mechanisms of peripheral tissues to prevent autoimmunity as compensatory roles for central tolerance. Antigen-specific peripheral tolerance is crucial to prevent the development of organ-specific autoimmunity. However, its function decoupled from thymic tolerance remains unclear. We used desmoglein 3 (Dsg3), a pemphigus antigen expressed in keratinocytes, to analyze peripheral tolerance under physiological antigen-expression conditions. Dsg3-deficient thymi were transplanted into athymic mice to create a unique condition in which Dsg3 was expressed only in peripheral tissue but not in the thymus. When bone marrow transfer was conducted from high-avidity Dsg3-specific T cell receptor–transgenic mice to thymus-transplanted mice, Dsg3-specific CD4+ T cells developed in the transplanted thymus but subsequently disappeared in the periphery. Additionally, when Dsg3-specific T cells developed in Dsg3−/− mice were adoptively transferred into Dsg3-sufficient recipients, the T cells disappeared in an antigen-specific manner without inducing autoimmune dermatitis. However, Dsg3-specific T cells overcame this disappearance and thus induced autoimmune dermatitis in Treg-ablated recipients but not in Foxp3-mutant recipients with dysfunctional Tregs. The molecules involved in disappearance were sought by screening the transcriptomes of wild-type and Foxp3-mutant Tregs. OX40 of Tregs was suggested to be responsible. Consistently, when OX40 expression of Tregs was constrained, Dsg3-specific T cells did not disappear. Furthermore, Tregs obtained OX40L from dendritic cells in an OX40-dependent manner in vitro and then suppressed OX40L expression in dendritic cells and Birc5 expression in Dsg3-specific T cells in vivo. Lastly, CRISPR/Cas9-mediated knockout of OX40 signaling in Dsg3-specific T cells restored their disappearance in Treg-ablated recipients. Thus, Treg-mediated peripheral deletion of autoreactive T cells operates as an OX40-dependent regulatory mechanism to avoid undesired autoimmunity besides thymic tolerance.
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16
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Cossarizza A, Chang HD, Radbruch A, Abrignani S, Addo R, Akdis M, Andrä I, Andreata F, Annunziato F, Arranz E, Bacher P, Bari S, Barnaba V, Barros-Martins J, Baumjohann D, Beccaria CG, Bernardo D, Boardman DA, Borger J, Böttcher C, Brockmann L, Burns M, Busch DH, Cameron G, Cammarata I, Cassotta A, Chang Y, Chirdo FG, Christakou E, Čičin-Šain L, Cook L, Corbett AJ, Cornelis R, Cosmi L, Davey MS, De Biasi S, De Simone G, del Zotto G, Delacher M, Di Rosa F, Di Santo J, Diefenbach A, Dong J, Dörner T, Dress RJ, Dutertre CA, Eckle SBG, Eede P, Evrard M, Falk CS, Feuerer M, Fillatreau S, Fiz-Lopez A, Follo M, Foulds GA, Fröbel J, Gagliani N, Galletti G, Gangaev A, Garbi N, Garrote JA, Geginat J, Gherardin NA, Gibellini L, Ginhoux F, Godfrey DI, Gruarin P, Haftmann C, Hansmann L, Harpur CM, Hayday AC, Heine G, Hernández DC, Herrmann M, Hoelsken O, Huang Q, Huber S, Huber JE, Huehn J, Hundemer M, Hwang WYK, Iannacone M, Ivison SM, Jäck HM, Jani PK, Keller B, Kessler N, Ketelaars S, Knop L, Knopf J, Koay HF, Kobow K, Kriegsmann K, Kristyanto H, Krueger A, Kuehne JF, Kunze-Schumacher H, Kvistborg P, Kwok I, Latorre D, et alCossarizza A, Chang HD, Radbruch A, Abrignani S, Addo R, Akdis M, Andrä I, Andreata F, Annunziato F, Arranz E, Bacher P, Bari S, Barnaba V, Barros-Martins J, Baumjohann D, Beccaria CG, Bernardo D, Boardman DA, Borger J, Böttcher C, Brockmann L, Burns M, Busch DH, Cameron G, Cammarata I, Cassotta A, Chang Y, Chirdo FG, Christakou E, Čičin-Šain L, Cook L, Corbett AJ, Cornelis R, Cosmi L, Davey MS, De Biasi S, De Simone G, del Zotto G, Delacher M, Di Rosa F, Di Santo J, Diefenbach A, Dong J, Dörner T, Dress RJ, Dutertre CA, Eckle SBG, Eede P, Evrard M, Falk CS, Feuerer M, Fillatreau S, Fiz-Lopez A, Follo M, Foulds GA, Fröbel J, Gagliani N, Galletti G, Gangaev A, Garbi N, Garrote JA, Geginat J, Gherardin NA, Gibellini L, Ginhoux F, Godfrey DI, Gruarin P, Haftmann C, Hansmann L, Harpur CM, Hayday AC, Heine G, Hernández DC, Herrmann M, Hoelsken O, Huang Q, Huber S, Huber JE, Huehn J, Hundemer M, Hwang WYK, Iannacone M, Ivison SM, Jäck HM, Jani PK, Keller B, Kessler N, Ketelaars S, Knop L, Knopf J, Koay HF, Kobow K, Kriegsmann K, Kristyanto H, Krueger A, Kuehne JF, Kunze-Schumacher H, Kvistborg P, Kwok I, Latorre D, Lenz D, Levings MK, Lino AC, Liotta F, Long HM, Lugli E, MacDonald KN, Maggi L, Maini MK, Mair F, Manta C, Manz RA, Mashreghi MF, Mazzoni A, McCluskey J, Mei HE, Melchers F, Melzer S, Mielenz D, Monin L, Moretta L, Multhoff G, Muñoz LE, Muñoz-Ruiz M, Muscate F, Natalini A, Neumann K, Ng LG, Niedobitek A, Niemz J, Almeida LN, Notarbartolo S, Ostendorf L, Pallett LJ, Patel AA, Percin GI, Peruzzi G, Pinti M, Pockley AG, Pracht K, Prinz I, Pujol-Autonell I, Pulvirenti N, Quatrini L, Quinn KM, Radbruch H, Rhys H, Rodrigo MB, Romagnani C, Saggau C, Sakaguchi S, Sallusto F, Sanderink L, Sandrock I, Schauer C, Scheffold A, Scherer HU, Schiemann M, Schildberg FA, Schober K, Schoen J, Schuh W, Schüler T, Schulz AR, Schulz S, Schulze J, Simonetti S, Singh J, Sitnik KM, Stark R, Starossom S, Stehle C, Szelinski F, Tan L, Tarnok A, Tornack J, Tree TIM, van Beek JJP, van de Veen W, van Gisbergen K, Vasco C, Verheyden NA, von Borstel A, Ward-Hartstonge KA, Warnatz K, Waskow C, Wiedemann A, Wilharm A, Wing J, Wirz O, Wittner J, Yang JHM, Yang J. Guidelines for the use of flow cytometry and cell sorting in immunological studies (third edition). Eur J Immunol 2021; 51:2708-3145. [PMID: 34910301 PMCID: PMC11115438 DOI: 10.1002/eji.202170126] [Show More Authors] [Citation(s) in RCA: 279] [Impact Index Per Article: 69.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
The third edition of Flow Cytometry Guidelines provides the key aspects to consider when performing flow cytometry experiments and includes comprehensive sections describing phenotypes and functional assays of all major human and murine immune cell subsets. Notably, the Guidelines contain helpful tables highlighting phenotypes and key differences between human and murine cells. Another useful feature of this edition is the flow cytometry analysis of clinical samples with examples of flow cytometry applications in the context of autoimmune diseases, cancers as well as acute and chronic infectious diseases. Furthermore, there are sections detailing tips, tricks and pitfalls to avoid. All sections are written and peer-reviewed by leading flow cytometry experts and immunologists, making this edition an essential and state-of-the-art handbook for basic and clinical researchers.
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Affiliation(s)
- Andrea Cossarizza
- Department of Medical and Surgical Sciences for Children & Adults, University of Modena and Reggio Emilia, Modena, Italy
| | - Hyun-Dong Chang
- German Rheumatism Research Center Berlin (DRFZ), Berlin, Germany
- Institute for Biotechnology, Technische Universität, Berlin, Germany
| | - Andreas Radbruch
- German Rheumatism Research Center Berlin (DRFZ), Berlin, Germany
| | - Sergio Abrignani
- Istituto Nazionale di Genetica Molecolare Romeo ed Enrica Invernizzi (INGM), Milan, Italy
- Department of Clinical Sciences and Community Health, Università degli Studi di Milano, Milan, Italy
| | - Richard Addo
- German Rheumatism Research Center Berlin (DRFZ), Berlin, Germany
| | - Mübeccel Akdis
- Swiss Institute of Allergy and Asthma Research (SIAF), University of Zurich, Davos, Switzerland
| | - Immanuel Andrä
- Institut für Medizinische Mikrobiologie, Immunologie und Hygiene, Technische Universität München, Munich, Germany
| | - Francesco Andreata
- Division of Immunology, Transplantation and Infectious Diseases, IRCSS San Raffaele Scientific Institute, Milan, Italy
| | - Francesco Annunziato
- Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy
| | - Eduardo Arranz
- Mucosal Immunology Lab, Unidad de Excelencia Instituto de Biomedicina y Genética Molecular de Valladolid (IBGM, Universidad de Valladolid-CSIC), Valladolid, Spain
| | - Petra Bacher
- Institute of Immunology, Christian-Albrechts Universität zu Kiel & Universitätsklinik Schleswig-Holstein, Kiel, Germany
- Institute of Clinical Molecular Biology Christian-Albrechts Universität zu Kiel, Kiel, Germany
| | - Sudipto Bari
- Division of Medical Sciences, National Cancer Centre Singapore, Singapore
- Cancer & Stem Cell Biology, Duke-NUS Medical School, Singapore, Singapore
| | - Vincenzo Barnaba
- Dipartimento di Medicina Interna e Specialità Mediche, Sapienza Università di Roma, Rome, Italy
- Center for Life Nano & Neuro Science@Sapienza, Istituto Italiano di Tecnologia (IIT), Rome, Italy
- Istituto Pasteur - Fondazione Cenci Bolognetti, Rome, Italy
| | | | - Dirk Baumjohann
- Medical Clinic III for Oncology, Hematology, Immuno-Oncology and Rheumatology, University Hospital Bonn, University of Bonn, Bonn, Germany
| | - Cristian G. Beccaria
- Division of Immunology, Transplantation and Infectious Diseases, IRCSS San Raffaele Scientific Institute, Milan, Italy
| | - David Bernardo
- Mucosal Immunology Lab, Unidad de Excelencia Instituto de Biomedicina y Genética Molecular de Valladolid (IBGM, Universidad de Valladolid-CSIC), Valladolid, Spain
- Centro de Investigaciones Biomédicas en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Madrid, Spain
| | - Dominic A. Boardman
- Department of Surgery, The University of British Columbia, Vancouver, Canada
- BC Children’s Hospital Research Institute, Vancouver, Canada
| | - Jessica Borger
- Department of Immunology and Pathology, Monash University, Melbourne, Victoria, Australia
| | - Chotima Böttcher
- Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin, Germany
| | - Leonie Brockmann
- Department of Microbiology & Immunology, Columbia University, New York City, USA
| | - Marie Burns
- German Rheumatism Research Center Berlin (DRFZ), Berlin, Germany
| | - Dirk H. Busch
- Institut für Medizinische Mikrobiologie, Immunologie und Hygiene, Technische Universität München, Munich, Germany
- German Center for Infection Research (DZIF), Munich, Germany
| | - Garth Cameron
- Department of Microbiology and Immunology, Peter Doherty Institute for Infection and Immunity, University of Melbourne, Melbourne, Victoria, Australia
- Australian Research Council Centre of Excellence in Advanced Molecular Imaging, University of Melbourne, Parkville, Victoria, Australia
| | - Ilenia Cammarata
- Dipartimento di Medicina Interna e Specialità Mediche, Sapienza Università di Roma, Rome, Italy
| | - Antonino Cassotta
- Institute for Research in Biomedicine, Università della Svizzera italiana, Bellinzona, Switzerland
| | - Yinshui Chang
- Medical Clinic III for Oncology, Hematology, Immuno-Oncology and Rheumatology, University Hospital Bonn, University of Bonn, Bonn, Germany
| | - Fernando Gabriel Chirdo
- Instituto de Estudios Inmunológicos y Fisiopatológicos - IIFP (UNLP-CONICET), Facultad de Ciencias Exactas, Universidad Nacional de La Plata, La Plata, Argentina
| | - Eleni Christakou
- Peter Gorer Department of Immunobiology, School of Immunology and Microbial Sciences, King’s College London, UK
- National Institute for Health Research (NIHR) Biomedical Research Center (BRC), Guy’s and St Thomas’ NHS Foundation Trust and King’s College London, London, UK
| | - Luka Čičin-Šain
- Department of Viral Immunology, Helmholtz Centre for Infection Research, Braunschweig, Germany
| | - Laura Cook
- BC Children’s Hospital Research Institute, Vancouver, Canada
- Department of Medicine, The University of British Columbia, Vancouver, Canada
| | - Alexandra J. Corbett
- Department of Microbiology and Immunology, Peter Doherty Institute for Infection and Immunity, University of Melbourne, Melbourne, Victoria, Australia
| | - Rebecca Cornelis
- German Rheumatism Research Center Berlin (DRFZ), Berlin, Germany
| | - Lorenzo Cosmi
- Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy
| | - Martin S. Davey
- Infection and Immunity Program, Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Clayton, Victoria, Australia
| | - Sara De Biasi
- Department of Medical and Surgical Sciences for Children & Adults, University of Modena and Reggio Emilia, Modena, Italy
| | - Gabriele De Simone
- Laboratory of Translational Immunology, IRCCS Humanitas Research Hospital, Rozzano, Milan, Italy
| | | | - Michael Delacher
- Institute for Immunology, University Medical Center Mainz, Mainz, Germany
- Research Centre for Immunotherapy, University Medical Center Mainz, Mainz, Germany
| | - Francesca Di Rosa
- Institute of Molecular Biology and Pathology, National Research Council of Italy (CNR), Rome, Italy
- Immunosurveillance Laboratory, The Francis Crick Institute, London, UK
| | - James Di Santo
- Innate Immunity Unit, Department of Immunology, Institut Pasteur, Paris, France
- Inserm U1223, Paris, France
| | - Andreas Diefenbach
- Laboratory of Innate Immunity, Department of Microbiology, Infectious Diseases and Immunology, Charité – Universitätsmedizin Berlin, Campus Benjamin Franklin, Berlin, Germany
- Mucosal and Developmental Immunology, German Rheumatism Research Center Berlin (DRFZ), Berlin, Germany
| | - Jun Dong
- Cell Biology, German Rheumatism Research Center Berlin (DRFZ), An Institute of the Leibniz Association, Berlin, Germany
| | - Thomas Dörner
- German Rheumatism Research Center Berlin (DRFZ), Berlin, Germany
- Department of Medicine/Rheumatology and Clinical Immunology, Charité Universitätsmedizin Berlin, Berlin, Germany
| | - Regine J. Dress
- Institute of Systems Immunology, Hamburg Center for Translational Immunology (HCTI), University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Charles-Antoine Dutertre
- Institut National de la Sante Et de la Recherce Medicale (INSERM) U1015, Equipe Labellisee-Ligue Nationale contre le Cancer, Villejuif, France
| | - Sidonia B. G. Eckle
- Department of Microbiology and Immunology, Peter Doherty Institute for Infection and Immunity, University of Melbourne, Melbourne, Victoria, Australia
| | - Pascale Eede
- Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin, Germany
| | - Maximilien Evrard
- Singapore Immunology Network (SIgN), Agency for Science, Technology and Research, Singapore, Singapore
| | - Christine S. Falk
- Institute of Transplant Immunology, Hannover Medical School, Hannover, Germany
| | - Markus Feuerer
- Regensburg Center for Interventional Immunology (RCI), Regensburg, Germany
- Chair for Immunology, University Regensburg, Regensburg, Germany
| | - Simon Fillatreau
- Institut Necker Enfants Malades, INSERM U1151-CNRS, UMR8253, Paris, France
- Université de Paris, Paris Descartes, Faculté de Médecine, Paris, France
- AP-HP, Hôpital Necker Enfants Malades, Paris, France
| | - Aida Fiz-Lopez
- Mucosal Immunology Lab, Unidad de Excelencia Instituto de Biomedicina y Genética Molecular de Valladolid (IBGM, Universidad de Valladolid-CSIC), Valladolid, Spain
| | - Marie Follo
- Department of Medicine I, Lighthouse Core Facility, Medical Center – University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
| | - Gemma A. Foulds
- John van Geest Cancer Research Centre, School of Science and Technology, Nottingham Trent University, Nottingham, UK
- Centre for Health, Ageing and Understanding Disease (CHAUD), School of Science and Technology, Nottingham Trent University, Nottingham, UK
| | - Julia Fröbel
- Immunology of Aging, Leibniz Institute on Aging – Fritz Lipmann Institute, Jena, Germany
| | - Nicola Gagliani
- Department of Medicine, Visceral and Thoracic Surgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
- Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
- Hamburg Center for Translational Immunology (HCTI), University Medical Center Hamburg-Eppendorf, Germany
| | - Giovanni Galletti
- Laboratory of Translational Immunology, IRCCS Humanitas Research Hospital, Rozzano, Milan, Italy
| | - Anastasia Gangaev
- Division of Molecular Oncology and Immunology, the Netherlands Cancer Institute, Amsterdam, The Netherlands
| | - Natalio Garbi
- Institute of Molecular Medicine and Experimental Immunology, Faculty of Medicine, University of Bonn, Germany
| | - José Antonio Garrote
- Mucosal Immunology Lab, Unidad de Excelencia Instituto de Biomedicina y Genética Molecular de Valladolid (IBGM, Universidad de Valladolid-CSIC), Valladolid, Spain
- Laboratory of Molecular Genetics, Servicio de Análisis Clínicos, Hospital Universitario Río Hortega, Gerencia Regional de Salud de Castilla y León (SACYL), Valladolid, Spain
| | - Jens Geginat
- Istituto Nazionale di Genetica Molecolare Romeo ed Enrica Invernizzi (INGM), Milan, Italy
- Department of Clinical Sciences and Community Health, Università degli Studi di Milano, Milan, Italy
| | - Nicholas A. Gherardin
- Department of Microbiology and Immunology, Peter Doherty Institute for Infection and Immunity, University of Melbourne, Melbourne, Victoria, Australia
- Australian Research Council Centre of Excellence in Advanced Molecular Imaging, University of Melbourne, Parkville, Victoria, Australia
| | - Lara Gibellini
- Department of Medical and Surgical Sciences for Children & Adults, University of Modena and Reggio Emilia, Modena, Italy
| | - Florent Ginhoux
- Singapore Immunology Network (SIgN), Agency for Science, Technology and Research, Singapore, Singapore
- Shanghai Institute of Immunology, Department of Immunology and Microbiology, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Translational Immunology Institute, SingHealth Duke-NUS Academic Medical Centre, Singapore, Singapore
| | - Dale I. Godfrey
- Department of Microbiology and Immunology, Peter Doherty Institute for Infection and Immunity, University of Melbourne, Melbourne, Victoria, Australia
- Australian Research Council Centre of Excellence in Advanced Molecular Imaging, University of Melbourne, Parkville, Victoria, Australia
| | - Paola Gruarin
- Istituto Nazionale di Genetica Molecolare Romeo ed Enrica Invernizzi (INGM), Milan, Italy
| | - Claudia Haftmann
- Institute of Experimental Immunology, University of Zurich, Zurich, Switzerland
| | - Leo Hansmann
- Department of Hematology, Oncology, and Tumor Immunology, Charité - Universitätsmedizin Berlin (CVK), Berlin, Germany
- Berlin Institute of Health (BIH), Berlin, Germany
- German Cancer Consortium (DKTK), partner site Berlin, Germany
| | - Christopher M. Harpur
- Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Clayton, Victoria, Australia
- Department of Molecular and Translational Sciences, Monash University, Clayton, Victoria, Australia
| | - Adrian C. Hayday
- Peter Gorer Department of Immunobiology, School of Immunology and Microbial Sciences, King’s College London, UK
- National Institute for Health Research (NIHR) Biomedical Research Center (BRC), Guy’s and St Thomas’ NHS Foundation Trust and King’s College London, London, UK
- Immunosurveillance Laboratory, The Francis Crick Institute, London, UK
| | - Guido Heine
- Division of Allergy, Department of Dermatology and Allergy, University Hospital Schleswig-Holstein, Kiel, Germany
| | - Daniela Carolina Hernández
- Innate Immunity, German Rheumatism Research Center Berlin (DRFZ), Berlin, Germany
- Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Department of Gastroenterology, Infectious Diseases, Rheumatology, Berlin, Germany
| | - Martin Herrmann
- Friedrich-Alexander-University Erlangen-Nürnberg (FAU), Department of Medicine 3 – Rheumatology and Immunology and Universitätsklinikum Erlangen, Erlangen, Germany
- Deutsches Zentrum für Immuntherapie, Friedrich-Alexander-University Erlangen-Nürnberg and Universitätsklinikum Erlangen, Erlangen, Germany
| | - Oliver Hoelsken
- Laboratory of Innate Immunity, Department of Microbiology, Infectious Diseases and Immunology, Charité – Universitätsmedizin Berlin, Campus Benjamin Franklin, Berlin, Germany
- Mucosal and Developmental Immunology, German Rheumatism Research Center Berlin (DRFZ), Berlin, Germany
| | - Qing Huang
- Department of Surgery, The University of British Columbia, Vancouver, Canada
- BC Children’s Hospital Research Institute, Vancouver, Canada
| | - Samuel Huber
- Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Johanna E. Huber
- Institute for Immunology, Biomedical Center, Faculty of Medicine, LMU Munich, Planegg-Martinsried, Germany
| | - Jochen Huehn
- Experimental Immunology, Helmholtz Centre for Infection Research, Braunschweig, Germany
| | - Michael Hundemer
- Department of Hematology, Oncology and Rheumatology, University Heidelberg, Heidelberg, Germany
| | - William Y. K. Hwang
- Cancer & Stem Cell Biology, Duke-NUS Medical School, Singapore, Singapore
- Department of Hematology, Singapore General Hospital, Singapore, Singapore
- Executive Offices, National Cancer Centre Singapore, Singapore
| | - Matteo Iannacone
- Division of Immunology, Transplantation and Infectious Diseases, IRCSS San Raffaele Scientific Institute, Milan, Italy
- Vita-Salute San Raffaele University, Milan, Italy
- Experimental Imaging Center, IRCCS San Raffaele Scientific Institute, Milan, Italy
| | - Sabine M. Ivison
- Department of Surgery, The University of British Columbia, Vancouver, Canada
- BC Children’s Hospital Research Institute, Vancouver, Canada
| | - Hans-Martin Jäck
- Division of Molecular Immunology, Nikolaus-Fiebiger-Center, Department of Internal Medicine III, University of Erlangen-Nürnberg, Erlangen, Germany
| | - Peter K. Jani
- German Rheumatism Research Center Berlin (DRFZ), Berlin, Germany
| | - Baerbel Keller
- Department of Rheumatology and Clinical Immunology, Medical Center – University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
- Center for Chronic Immunodeficiency, Medical Center – University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
| | - Nina Kessler
- Institute of Molecular Medicine and Experimental Immunology, Faculty of Medicine, University of Bonn, Germany
| | - Steven Ketelaars
- Division of Molecular Oncology and Immunology, the Netherlands Cancer Institute, Amsterdam, The Netherlands
| | - Laura Knop
- Institute of Molecular and Clinical Immunology, Otto-von-Guericke University, Magdeburg, Germany
| | - Jasmin Knopf
- Friedrich-Alexander-University Erlangen-Nürnberg (FAU), Department of Medicine 3 – Rheumatology and Immunology and Universitätsklinikum Erlangen, Erlangen, Germany
- Deutsches Zentrum für Immuntherapie, Friedrich-Alexander-University Erlangen-Nürnberg and Universitätsklinikum Erlangen, Erlangen, Germany
| | - Hui-Fern Koay
- Department of Microbiology and Immunology, Peter Doherty Institute for Infection and Immunity, University of Melbourne, Melbourne, Victoria, Australia
- Australian Research Council Centre of Excellence in Advanced Molecular Imaging, University of Melbourne, Parkville, Victoria, Australia
| | - Katja Kobow
- Department of Neuropathology, Universitätsklinikum Erlangen, Germany
| | - Katharina Kriegsmann
- Department of Hematology, Oncology and Rheumatology, University Heidelberg, Heidelberg, Germany
| | - H. Kristyanto
- Department of Rheumatology, Leiden University Medical Center, Leiden, The Netherlands
| | - Andreas Krueger
- Institute for Molecular Medicine, Goethe University Frankfurt, Frankfurt am Main, Germany
| | - Jenny F. Kuehne
- Institute of Transplant Immunology, Hannover Medical School, Hannover, Germany
| | - Heike Kunze-Schumacher
- Institute for Molecular Medicine, Goethe University Frankfurt, Frankfurt am Main, Germany
| | - Pia Kvistborg
- Division of Molecular Oncology and Immunology, the Netherlands Cancer Institute, Amsterdam, The Netherlands
| | - Immanuel Kwok
- Singapore Immunology Network (SIgN), Agency for Science, Technology and Research, Singapore, Singapore
| | | | - Daniel Lenz
- German Rheumatism Research Center Berlin (DRFZ), Berlin, Germany
| | - Megan K. Levings
- Department of Surgery, The University of British Columbia, Vancouver, Canada
- BC Children’s Hospital Research Institute, Vancouver, Canada
- School of Biomedical Engineering, The University of British Columbia, Vancouver, Canada
| | - Andreia C. Lino
- German Rheumatism Research Center Berlin (DRFZ), Berlin, Germany
| | - Francesco Liotta
- Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy
| | - Heather M. Long
- Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, UK
| | - Enrico Lugli
- Laboratory of Translational Immunology, IRCCS Humanitas Research Hospital, Rozzano, Milan, Italy
| | - Katherine N. MacDonald
- BC Children’s Hospital Research Institute, Vancouver, Canada
- School of Biomedical Engineering, The University of British Columbia, Vancouver, Canada
- Michael Smith Laboratories, The University of British Columbia, Vancouver, Canada
| | - Laura Maggi
- Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy
| | - Mala K. Maini
- Division of Infection & Immunity, Institute of Immunity & Transplantation, University College London, London, UK
| | - Florian Mair
- Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
| | - Calin Manta
- Department of Hematology, Oncology and Rheumatology, University Heidelberg, Heidelberg, Germany
| | - Rudolf Armin Manz
- Institute for Systemic Inflammation Research, University of Luebeck, Luebeck, Germany
| | | | - Alessio Mazzoni
- Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy
| | - James McCluskey
- Department of Microbiology and Immunology, Peter Doherty Institute for Infection and Immunity, University of Melbourne, Melbourne, Victoria, Australia
| | - Henrik E. Mei
- German Rheumatism Research Center Berlin (DRFZ), Berlin, Germany
| | - Fritz Melchers
- German Rheumatism Research Center Berlin (DRFZ), Berlin, Germany
| | - Susanne Melzer
- Clinical Trial Center Leipzig, Leipzig University, Härtelstr.16, −18, Leipzig, 04107, Germany
| | - Dirk Mielenz
- Division of Molecular Immunology, Nikolaus-Fiebiger-Center, Department of Internal Medicine III, University of Erlangen-Nürnberg, Erlangen, Germany
| | - Leticia Monin
- Immunosurveillance Laboratory, The Francis Crick Institute, London, UK
| | - Lorenzo Moretta
- Department of Immunology, IRCCS Bambino Gesù Children’s Hospital, Rome, Italy
| | - Gabriele Multhoff
- Radiation Immuno-Oncology Group, Center for Translational Cancer Research (TranslaTUM), Technical University of Munich (TUM), Klinikum rechts der Isar, Munich, Germany
- Department of Radiation Oncology, Technical University of Munich (TUM), Klinikum rechts der Isar, Munich, Germany
| | - Luis Enrique Muñoz
- Friedrich-Alexander-University Erlangen-Nürnberg (FAU), Department of Medicine 3 – Rheumatology and Immunology and Universitätsklinikum Erlangen, Erlangen, Germany
- Deutsches Zentrum für Immuntherapie, Friedrich-Alexander-University Erlangen-Nürnberg and Universitätsklinikum Erlangen, Erlangen, Germany
| | - Miguel Muñoz-Ruiz
- Immunosurveillance Laboratory, The Francis Crick Institute, London, UK
| | - Franziska Muscate
- Department of Medicine, Visceral and Thoracic Surgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
- Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Ambra Natalini
- Institute of Molecular Biology and Pathology, National Research Council of Italy (CNR), Rome, Italy
| | - Katrin Neumann
- Institute of Experimental Immunology and Hepatology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Lai Guan Ng
- Division of Medical Sciences, National Cancer Centre Singapore, Singapore
- Singapore Immunology Network (SIgN), Agency for Science, Technology and Research, Singapore, Singapore
- Department of Microbiology & Immunology, Immunology Programme, Life Science Institute, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
- School of Biological Sciences, Nanyang Technological University, Singapore, Singapore
| | | | - Jana Niemz
- Experimental Immunology, Helmholtz Centre for Infection Research, Braunschweig, Germany
| | | | - Samuele Notarbartolo
- Istituto Nazionale di Genetica Molecolare Romeo ed Enrica Invernizzi (INGM), Milan, Italy
| | - Lennard Ostendorf
- Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin, Germany
| | - Laura J. Pallett
- Division of Infection & Immunity, Institute of Immunity & Transplantation, University College London, London, UK
| | - Amit A. Patel
- Institut National de la Sante Et de la Recherce Medicale (INSERM) U1015, Equipe Labellisee-Ligue Nationale contre le Cancer, Villejuif, France
| | - Gulce Itir Percin
- Immunology of Aging, Leibniz Institute on Aging – Fritz Lipmann Institute, Jena, Germany
| | - Giovanna Peruzzi
- Center for Life Nano & Neuro Science@Sapienza, Istituto Italiano di Tecnologia (IIT), Rome, Italy
| | - Marcello Pinti
- Department of Life Sciences, University of Modena and Reggio Emilia, Modena, Italy
| | - A. Graham Pockley
- John van Geest Cancer Research Centre, School of Science and Technology, Nottingham Trent University, Nottingham, UK
- Centre for Health, Ageing and Understanding Disease (CHAUD), School of Science and Technology, Nottingham Trent University, Nottingham, UK
| | - Katharina Pracht
- Division of Molecular Immunology, Nikolaus-Fiebiger-Center, Department of Internal Medicine III, University of Erlangen-Nürnberg, Erlangen, Germany
| | - Immo Prinz
- Institute of Immunology, Hannover Medical School, Hannover, Germany
- Institute of Systems Immunology, Hamburg Center for Translational Immunology (HCTI), University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Irma Pujol-Autonell
- National Institute for Health Research (NIHR) Biomedical Research Center (BRC), Guy’s and St Thomas’ NHS Foundation Trust and King’s College London, London, UK
- Peter Gorer Department of Immunobiology, King’s College London, London, UK
| | - Nadia Pulvirenti
- Istituto Nazionale di Genetica Molecolare Romeo ed Enrica Invernizzi (INGM), Milan, Italy
| | - Linda Quatrini
- Department of Immunology, IRCCS Bambino Gesù Children’s Hospital, Rome, Italy
| | - Kylie M. Quinn
- School of Biomedical and Health Sciences, RMIT University, Bundorra, Victoria, Australia
- Department of Biochemistry and Molecular Biology, Monash University, Clayton, Victoria, Australia
| | - Helena Radbruch
- Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin, Germany
| | - Hefin Rhys
- Flow Cytometry Science Technology Platform, The Francis Crick Institute, London, UK
| | - Maria B. Rodrigo
- Institute of Molecular Medicine and Experimental Immunology, Faculty of Medicine, University of Bonn, Germany
| | - Chiara Romagnani
- Innate Immunity, German Rheumatism Research Center Berlin (DRFZ), Berlin, Germany
- Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Department of Gastroenterology, Infectious Diseases, Rheumatology, Berlin, Germany
| | - Carina Saggau
- Institute of Immunology, Christian-Albrechts Universität zu Kiel & Universitätsklinik Schleswig-Holstein, Kiel, Germany
| | | | - Federica Sallusto
- Institute for Research in Biomedicine, Università della Svizzera italiana, Bellinzona, Switzerland
- Institute of Microbiology, ETH Zurich, Zurich, Switzerland
| | - Lieke Sanderink
- Regensburg Center for Interventional Immunology (RCI), Regensburg, Germany
- Chair for Immunology, University Regensburg, Regensburg, Germany
| | - Inga Sandrock
- Institute of Immunology, Hannover Medical School, Hannover, Germany
| | - Christine Schauer
- Friedrich-Alexander-University Erlangen-Nürnberg (FAU), Department of Medicine 3 – Rheumatology and Immunology and Universitätsklinikum Erlangen, Erlangen, Germany
- Deutsches Zentrum für Immuntherapie, Friedrich-Alexander-University Erlangen-Nürnberg and Universitätsklinikum Erlangen, Erlangen, Germany
| | - Alexander Scheffold
- Institute of Immunology, Christian-Albrechts Universität zu Kiel & Universitätsklinik Schleswig-Holstein, Kiel, Germany
| | - Hans U. Scherer
- Department of Rheumatology, Leiden University Medical Center, Leiden, The Netherlands
| | - Matthias Schiemann
- Institut für Medizinische Mikrobiologie, Immunologie und Hygiene, Technische Universität München, Munich, Germany
| | - Frank A. Schildberg
- Clinic for Orthopedics and Trauma Surgery, University Hospital Bonn, Bonn, Germany
| | - Kilian Schober
- Institut für Medizinische Mikrobiologie, Immunologie und Hygiene, Technische Universität München, Munich, Germany
- Mikrobiologisches Institut – Klinische Mikrobiologie, Immunologie und Hygiene, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität (FAU) Erlangen-Nürnberg, Germany
| | - Janina Schoen
- Friedrich-Alexander-University Erlangen-Nürnberg (FAU), Department of Medicine 3 – Rheumatology and Immunology and Universitätsklinikum Erlangen, Erlangen, Germany
- Deutsches Zentrum für Immuntherapie, Friedrich-Alexander-University Erlangen-Nürnberg and Universitätsklinikum Erlangen, Erlangen, Germany
| | - Wolfgang Schuh
- Division of Molecular Immunology, Nikolaus-Fiebiger-Center, Department of Internal Medicine III, University of Erlangen-Nürnberg, Erlangen, Germany
| | - Thomas Schüler
- Institute of Molecular and Clinical Immunology, Otto-von-Guericke University, Magdeburg, Germany
| | - Axel R. Schulz
- German Rheumatism Research Center Berlin (DRFZ), Berlin, Germany
| | - Sebastian Schulz
- Division of Molecular Immunology, Nikolaus-Fiebiger-Center, Department of Internal Medicine III, University of Erlangen-Nürnberg, Erlangen, Germany
| | - Julia Schulze
- German Rheumatism Research Center Berlin (DRFZ), Berlin, Germany
| | - Sonia Simonetti
- Institute of Molecular Biology and Pathology, National Research Council of Italy (CNR), Rome, Italy
| | - Jeeshan Singh
- Friedrich-Alexander-University Erlangen-Nürnberg (FAU), Department of Medicine 3 – Rheumatology and Immunology and Universitätsklinikum Erlangen, Erlangen, Germany
- Deutsches Zentrum für Immuntherapie, Friedrich-Alexander-University Erlangen-Nürnberg and Universitätsklinikum Erlangen, Erlangen, Germany
| | - Katarzyna M. Sitnik
- Department of Viral Immunology, Helmholtz Centre for Infection Research, Braunschweig, Germany
| | - Regina Stark
- Charité Universitätsmedizin Berlin – BIH Center for Regenerative Therapies, Berlin, Germany
- Sanquin Research – Adaptive Immunity, Amsterdam, The Netherlands
| | - Sarah Starossom
- Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin, Germany
| | - Christina Stehle
- Innate Immunity, German Rheumatism Research Center Berlin (DRFZ), Berlin, Germany
- Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Department of Gastroenterology, Infectious Diseases, Rheumatology, Berlin, Germany
| | - Franziska Szelinski
- German Rheumatism Research Center Berlin (DRFZ), Berlin, Germany
- Department of Medicine/Rheumatology and Clinical Immunology, Charité Universitätsmedizin Berlin, Berlin, Germany
| | - Leonard Tan
- Singapore Immunology Network (SIgN), Agency for Science, Technology and Research, Singapore, Singapore
- Department of Microbiology & Immunology, Immunology Programme, Life Science Institute, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Attila Tarnok
- Institute for Medical Informatics, Statistics and Epidemiology (IMISE), University of Leipzig, Leipzig, Germany
- Department of Precision Instrument, Tsinghua University, Beijing, China
- Department of Preclinical Development and Validation, Fraunhofer Institute for Cell Therapy and Immunology IZI, Leipzig, Germany
| | - Julia Tornack
- German Rheumatism Research Center Berlin (DRFZ), Berlin, Germany
| | - Timothy I. M. Tree
- Peter Gorer Department of Immunobiology, School of Immunology and Microbial Sciences, King’s College London, UK
- National Institute for Health Research (NIHR) Biomedical Research Center (BRC), Guy’s and St Thomas’ NHS Foundation Trust and King’s College London, London, UK
| | - Jasper J. P. van Beek
- Laboratory of Translational Immunology, IRCCS Humanitas Research Hospital, Rozzano, Milan, Italy
| | - Willem van de Veen
- Swiss Institute of Allergy and Asthma Research (SIAF), University of Zurich, Davos, Switzerland
| | | | - Chiara Vasco
- Istituto Nazionale di Genetica Molecolare Romeo ed Enrica Invernizzi (INGM), Milan, Italy
| | - Nikita A. Verheyden
- Institute for Molecular Medicine, Goethe University Frankfurt, Frankfurt am Main, Germany
| | - Anouk von Borstel
- Infection and Immunity Program, Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Clayton, Victoria, Australia
| | - Kirsten A. Ward-Hartstonge
- Department of Surgery, The University of British Columbia, Vancouver, Canada
- BC Children’s Hospital Research Institute, Vancouver, Canada
| | - Klaus Warnatz
- Department of Rheumatology and Clinical Immunology, Medical Center – University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
- Center for Chronic Immunodeficiency, Medical Center – University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
| | - Claudia Waskow
- Immunology of Aging, Leibniz Institute on Aging – Fritz Lipmann Institute, Jena, Germany
- Institute of Biochemistry and Biophysics, Faculty of Biological Sciences, Friedrich-Schiller-University Jena, Jena, Germany
- Department of Medicine III, Technical University Dresden, Dresden, Germany
| | - Annika Wiedemann
- German Rheumatism Research Center Berlin (DRFZ), Berlin, Germany
- Department of Medicine/Rheumatology and Clinical Immunology, Charité Universitätsmedizin Berlin, Berlin, Germany
| | - Anneke Wilharm
- Institute of Immunology, Hannover Medical School, Hannover, Germany
| | - James Wing
- Immunology Frontier Research Center, Osaka University, Japan
| | - Oliver Wirz
- Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA
| | - Jens Wittner
- Division of Molecular Immunology, Nikolaus-Fiebiger-Center, Department of Internal Medicine III, University of Erlangen-Nürnberg, Erlangen, Germany
| | - Jennie H. M. Yang
- Peter Gorer Department of Immunobiology, School of Immunology and Microbial Sciences, King’s College London, UK
- National Institute for Health Research (NIHR) Biomedical Research Center (BRC), Guy’s and St Thomas’ NHS Foundation Trust and King’s College London, London, UK
| | - Juhao Yang
- Experimental Immunology, Helmholtz Centre for Infection Research, Braunschweig, Germany
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Fu Y, Wang L, Liu W, Yang L, Li L, Wang L, Sun X, Zhang ZR, Lin Q, Zhang L. OX40L blockade cellular nanovesicles for autoimmune diseases therapy. J Control Release 2021; 337:557-570. [PMID: 34371056 DOI: 10.1016/j.jconrel.2021.08.008] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2021] [Revised: 08/03/2021] [Accepted: 08/04/2021] [Indexed: 12/13/2022]
Abstract
Current clinical agents for autoimmunity disorders treatment often cause substantial adverse effects and safety concerns, owing to non-specific immune modulation. Due to the prominent contribution of effector T cells in pathogenesis of rheumatoid arthritis (RA) and inflammatory bowel disease (IBD), and preferential location of co-stimulatory receptor-ligand pair OX40-OX40L at the inflamed sites, selectively targeting autoaggressive T cells by blockade OX40-OX40L, might represent an alternative strategy. Herein, we developed a new strategy to antagonize OX40-OX40L interaction by engineering a cell membrane derived nanovesicles (NVs) expressing OX40 receptors (OX40 NVs), and explored their potential for autoimmune disorders therapy. OX40 NVs showed specific binding capability to inflamed HUVECs in vitro, it also possessed distinct arthritic-targeting capacity in RA inflamed joints, and preferential accumulation in IBD inflamed colon. OX40 NVs efficiently suppressed the progression of both RA and IBD diseases through reducing CD4+OX40+ T cells population, and proinflammatory cytokines (i.e., TNF-α and IL-1β), while reinforcing Tregs immune-suppressive effect, with superior therapeutic efficacy than anti-OX40L. Additionally, dexamethasone (DEX) loading can further enhance the potential of OX40 NVs for RA treatment. Owing to their preferential localization to inflamed sites, and potent immune-suppression ability, targeting OX40-OX40L blockade by OX40 NVs for autoimmune therapy is highly promising.
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Affiliation(s)
- Yu Fu
- College of Polymer Science and Engineering, Key Laboratory of Drug Targeting and Drug Delivery System of the Education Ministry, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, 640041, china; College of Pharmaceutical Sciences, Southwest University, 400715, China
| | - Leilei Wang
- College of Polymer Science and Engineering, Key Laboratory of Drug Targeting and Drug Delivery System of the Education Ministry, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, 640041, china
| | - Wei Liu
- College of Polymer Science and Engineering, Key Laboratory of Drug Targeting and Drug Delivery System of the Education Ministry, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, 640041, china
| | - Lan Yang
- College of Polymer Science and Engineering, Key Laboratory of Drug Targeting and Drug Delivery System of the Education Ministry, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, 640041, china
| | - Lin Li
- College of Polymer Science and Engineering, Key Laboratory of Drug Targeting and Drug Delivery System of the Education Ministry, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, 640041, china
| | - Luyao Wang
- College of Polymer Science and Engineering, Key Laboratory of Drug Targeting and Drug Delivery System of the Education Ministry, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, 640041, china
| | - Xun Sun
- College of Polymer Science and Engineering, Key Laboratory of Drug Targeting and Drug Delivery System of the Education Ministry, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, 640041, china
| | - Zhi-Rong Zhang
- College of Polymer Science and Engineering, Key Laboratory of Drug Targeting and Drug Delivery System of the Education Ministry, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, 640041, china
| | - Qing Lin
- College of Polymer Science and Engineering, Key Laboratory of Drug Targeting and Drug Delivery System of the Education Ministry, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, 640041, china.
| | - Ling Zhang
- College of Polymer Science and Engineering, Key Laboratory of Drug Targeting and Drug Delivery System of the Education Ministry, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, 640041, china.
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Rindler K, Krausgruber T, Thaler FM, Alkon N, Bangert C, Kurz H, Fortelny N, Rojahn TB, Jonak C, Griss J, Bock C, Brunner PM. Spontaneously Resolved Atopic Dermatitis Shows Melanocyte and Immune Cell Activation Distinct From Healthy Control Skin. Front Immunol 2021; 12:630892. [PMID: 33717163 PMCID: PMC7943477 DOI: 10.3389/fimmu.2021.630892] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2020] [Accepted: 02/01/2021] [Indexed: 01/11/2023] Open
Abstract
Atopic dermatitis (AD) typically starts in infancy or early childhood, showing spontaneous remission in a subset of patients, while others develop lifelong disease. Despite an increased understanding of AD, factors guiding its natural course are only insufficiently elucidated. We thus performed suction blistering in skin of adult patients with stable, spontaneous remission from previous moderate-to-severe AD during childhood. Samples were compared to healthy controls without personal or familial history of atopy, and to chronic, active AD lesions. Skin cells and tissue fluid obtained were used for single-cell RNA sequencing and proteomic multiplex assays, respectively. We found overall cell composition and proteomic profiles of spontaneously healed AD to be comparable to healthy control skin, without upregulation of typical AD activity markers (e.g., IL13, S100As, and KRT16). Among all cell types in spontaneously healed AD, melanocytes harbored the largest numbers of differentially expressed genes in comparison to healthy controls, with upregulation of potentially anti-inflammatory markers such as PLA2G7. Conventional T-cells also showed increases in regulatory markers, and a general skewing toward a more Th1-like phenotype. By contrast, gene expression of regulatory T-cells and keratinocytes was essentially indistinguishable from healthy skin. Melanocytes and conventional T-cells might thus contribute a specific regulatory milieu in spontaneously healed AD skin.
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Affiliation(s)
- Katharina Rindler
- Department of Dermatology, Medical University of Vienna, Vienna, Austria
| | - Thomas Krausgruber
- CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria
| | - Felix M. Thaler
- Department of Dermatology, Medical University of Vienna, Vienna, Austria
| | - Natalia Alkon
- Department of Dermatology, Medical University of Vienna, Vienna, Austria
| | - Christine Bangert
- Department of Dermatology, Medical University of Vienna, Vienna, Austria
| | - Harald Kurz
- Department of Dermatology, Medical University of Vienna, Vienna, Austria
| | - Nikolaus Fortelny
- CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria
| | - Thomas B. Rojahn
- Department of Dermatology, Medical University of Vienna, Vienna, Austria
| | - Constanze Jonak
- Department of Dermatology, Medical University of Vienna, Vienna, Austria
| | - Johannes Griss
- Department of Dermatology, Medical University of Vienna, Vienna, Austria
| | - Christoph Bock
- CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria
- Center for Medical Statistics, Informatics, and Intelligent Systems, Institute of Artificial Intelligence and Decision Support, Medical University of Vienna, Vienna, Austria
| | - Patrick M. Brunner
- Department of Dermatology, Medical University of Vienna, Vienna, Austria
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19
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Kojima H, Kashiwakura Y, Kanno Y, Hashiguchi M, Kobata T. Fine-tuning of antigen-specific immune responses by regulatory T cells activated via antigen recognition-independent and humoral factor-dependent mechanisms. Scand J Immunol 2021; 93:e13020. [PMID: 33393095 DOI: 10.1111/sji.13020] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2020] [Revised: 12/21/2020] [Accepted: 12/29/2020] [Indexed: 11/28/2022]
Abstract
CD4+ CD25+ Foxp3+ regulatory T cells (Tregs) are highly sensitive to IL-2, one of the many cytokines produced during immune responses, for their development, survival and functions. Although the effects of IL-2 administration on Tregs in vivo are well characterized, the effects on Tregs elicited by IL-2 produced during an immune response have not been elucidated. Hence, in this study, Treg behaviour during IL-2-producing immune responses was explored using in vivo and in vitro murine systems. The use of murine mixed lymphocyte culture (MLC) revealed that a large proportion of Tregs increased in size, accompanied by both cell death and proliferation status. Further, these large Tregs, which were found to not recognize specific antigens, were observed in MLCs as being functionally activated by various cytokines, including IL-2, produced by antigen-specific T cells. This 'bystander Treg activation' was also observed in mice with graft-versus-host reactions (GvHRs). Alternatively, effector cells from Treg-depleted MLCs exhibited lower antigen-specific responses or higher cross-reactivity as compared to control MLCs with Tregs. Taken together, these results suggest that Tregs are activated by cytokines, mainly IL-2, released from T cells that are activated by a specific antigen. Subsequently, these activated bystander Tregs contribute to the fine-tuning of highly antigen-specific immune responses.
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Affiliation(s)
- Hidefumi Kojima
- Department of Immunology, Dokkyo Medical University School of Medicine, Tochigi, Japan.,Division of Host Defense, Research Center for Advanced Medical Science, Dokkyo Medical University School of Medicine, Tochigi, Japan
| | - Yuji Kashiwakura
- Department of Immunology, Dokkyo Medical University School of Medicine, Tochigi, Japan
| | - Yumiko Kanno
- Department of Immunology, Dokkyo Medical University School of Medicine, Tochigi, Japan.,Division of Host Defense, Research Center for Advanced Medical Science, Dokkyo Medical University School of Medicine, Tochigi, Japan
| | - Masaaki Hashiguchi
- Department of Immunology, Dokkyo Medical University School of Medicine, Tochigi, Japan.,Division of Host Defense, Research Center for Advanced Medical Science, Dokkyo Medical University School of Medicine, Tochigi, Japan
| | - Tetsuji Kobata
- Department of Immunology, Dokkyo Medical University School of Medicine, Tochigi, Japan
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20
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Abstract
Mucosal surfaces are distinctive sites exposed to environmental, dietary, and microbial antigens. Particularly in the gut, the host continuously actively adapts via complex interactions between the microbiota and dietary compounds and immune and other tissue cells. Regulatory T cells (Tregs) are critical for tuning the intestinal immune response to self- and non-self-antigens in the intestine. Its importance in intestinal homeostasis is illustrated by the onset of overt inflammation caused by deficiency in Treg generation, function, or stability in the gut. A substantial imbalance in Tregs has been observed in intestinal tissue during pathogenic conditions, when a tightly regulated and equilibrated system becomes dysregulated and leads to unimpeded and chronic immune responses. In this chapter, we compile and critically discuss the current knowledge on the key factors that promote Treg-mediated tolerance in the gut, such as those involved in intestinal Treg differentiation, specificity and suppressive function, and their immunophenotype during health and disease. We also discuss the current state of knowledge on Treg dysregulation in human intestine during pathological states such as inflammatory bowel disease (IBD), necrotizing enterocolitis (NEC), graft-versus-host disease (GVHD), and colorectal cancer (CRC), and how that knowledge is guiding development of Treg-targeted therapies to treat or prevent intestinal disorders.
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21
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Chen S, Zhang L, Ying Y, Wang Y, Arnold PR, Wang G, Li J, Ghobrial RM, Chen W, Xiao X, Li XC. Epigenetically modifying the Foxp3 locus for generation of stable antigen-specific Tregs as cellular therapeutics. Am J Transplant 2020; 20:2366-2379. [PMID: 32167228 PMCID: PMC7483360 DOI: 10.1111/ajt.15845] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2019] [Revised: 02/14/2020] [Accepted: 02/25/2020] [Indexed: 01/25/2023]
Abstract
Foxp3+ regulatory T cells (Tregs) are potent immunoregulatory cells, prompting strong interests in manipulating them for therapeutic purposes. However, significant challenges remain, including their heterogeneity and functional instability. Here we focused on the inducible Tregs (iTregs) and studied whether the Foxp3 locus can be epigenetically edited ex vivo to produce stable therapeutic iTregs. Under iTreg-inducing condition where activated CD4+ T effector cells were converted to Foxp3+ Tregs, we tested approximately 30 compounds and identified 3 chromatin-modifying chemical compounds (3C) consisting of sodium butyrate (a broad histone deacetylase inhibitor), UNC0646 (a histone methyltransferase inhibitor), and vitamin C (a TET dioxygenase co-activator), that together produced complete demethylation at the conserved noncoding sequence 2 (CNS2) region of Foxp3 locus. We found that iTregs induced in the presence of 3C (3C-iTregs) are stable, even after exposure to inflammatory cytokines. They expressed high levels of Foxp3 and exhibited potent suppressive activities both in vitro and in vivo. We showed that in models of autoimmunity and transplant rejection, adoptive transfer of antigen-specific 3C-iTregs prevented the induction of experimental autoimmune encephalitis and enabled long-term skin allograft survival. Our data demonstrate that the Foxp3 locus can be epigenetically edited ex vivo to generate stable therapeutic iTregs.
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Affiliation(s)
- Shuqiu Chen
- Immunobiology & Transplant Science Center and Department of Surgery, Houston Methodist Hospital, Houston, Texas,Department of Urology, Zhongda Hospital, Southeast University, Nanjing, China
| | - Lei Zhang
- Immunobiology & Transplant Science Center and Department of Surgery, Houston Methodist Hospital, Houston, Texas
| | - Yuanlin Ying
- Immunobiology & Transplant Science Center and Department of Surgery, Houston Methodist Hospital, Houston, Texas
| | - Yixuan Wang
- Immunobiology & Transplant Science Center and Department of Surgery, Houston Methodist Hospital, Houston, Texas
| | - Preston R. Arnold
- Immunobiology & Transplant Science Center and Department of Surgery, Houston Methodist Hospital, Houston, Texas
| | - Guangchuan Wang
- Immunobiology & Transplant Science Center and Department of Surgery, Houston Methodist Hospital, Houston, Texas
| | - Junhui Li
- Immunobiology & Transplant Science Center and Department of Surgery, Houston Methodist Hospital, Houston, Texas
| | - Rafik M. Ghobrial
- Immunobiology & Transplant Science Center and Department of Surgery, Houston Methodist Hospital, Houston, Texas,Department of Surgery, Weill Cornell Medicine of Cornell University, New York, New York
| | - Wenhao Chen
- Immunobiology & Transplant Science Center and Department of Surgery, Houston Methodist Hospital, Houston, Texas,Department of Surgery, Weill Cornell Medicine of Cornell University, New York, New York
| | - Xiang Xiao
- Immunobiology & Transplant Science Center and Department of Surgery, Houston Methodist Hospital, Houston, Texas
| | - Xian C. Li
- Immunobiology & Transplant Science Center and Department of Surgery, Houston Methodist Hospital, Houston, Texas,Department of Surgery, Weill Cornell Medicine of Cornell University, New York, New York
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22
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Advances in Anti-Cancer Immunotherapy: Car-T Cell, Checkpoint Inhibitors, Dendritic Cell Vaccines, and Oncolytic Viruses, and Emerging Cellular and Molecular Targets. Cancers (Basel) 2020; 12:cancers12071826. [PMID: 32645977 PMCID: PMC7408985 DOI: 10.3390/cancers12071826] [Citation(s) in RCA: 54] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2020] [Revised: 06/21/2020] [Accepted: 06/23/2020] [Indexed: 12/12/2022] Open
Abstract
Unlike traditional cancer therapies, such as surgery, radiation and chemotherapy that are typically non-specific, cancer immunotherapy harnesses the high specificity of a patient’s own immune system to selectively kill cancer cells. The immune system is the body’s main cancer surveillance system, but cancers may evade destruction thanks to various immune-suppressing mechanisms. We therefore need to deploy various immunotherapy-based strategies to help bolster the anti-tumour immune responses. These include engineering T cells to express chimeric antigen receptors (CARs) to specifically recognise tumour neoantigens, inactivating immune checkpoints, oncolytic viruses and dendritic cell (DC) vaccines, which have all shown clinical benefit in certain cancers. However, treatment efficacy remains poor due to drug-induced adverse events and immunosuppressive tendencies of the tumour microenvironment. Recent preclinical studies have unveiled novel therapies such as anti-cathepsin antibodies, galectin-1 blockade and anti-OX40 agonistic antibodies, which may be utilised as adjuvant therapies to modulate the tumour microenvironment and permit more ferocious anti-tumour immune response.
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23
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Mandatori S, Pacella I, Marzolla V, Mammi C, Starace D, Padula F, Vitiello L, Armani A, Savoia C, Taurino M, De Zio D, Giampietri C, Piconese S, Cecconi F, Caprio M, Filippini A. Altered Tregs Differentiation and Impaired Autophagy Correlate to Atherosclerotic Disease. Front Immunol 2020; 11:350. [PMID: 32231663 PMCID: PMC7082762 DOI: 10.3389/fimmu.2020.00350] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2019] [Accepted: 02/13/2020] [Indexed: 12/21/2022] Open
Abstract
Atherosclerosis is a progressive vascular disease representing the primary cause of morbidity and mortality in developed countries. Formerly, atherosclerosis was considered as a mere passive accumulation of lipids in blood vessels. However, it is now clear that atherosclerosis is a complex and multifactorial disease, in which the involvement of immune cells and inflammation play a key role. A variety of studies have shown that autophagy-a cellular catalytic mechanism able to remove injured cytoplasmic components in response to cellular stress-may be proatherogenic. So far, in this context, its role has been investigated in smooth muscle cells, macrophages, and endothelial cells, while the function of this catabolic protective process in lymphocyte functionality has been overlooked. The few studies carried out so far, however, suggested that autophagy modulation in lymphocyte subsets may be functionally related to plaque formation and development. Therefore, in this research, we aimed at better clarifying the role of lymphocyte subsets, mainly regulatory T cells (Tregs), in human atherosclerotic plaques and in animal models of atherosclerosis investigating the contribution of autophagy on immune cell homeostasis. Here, we investigate basal autophagy in a mouse model of atherosclerosis, apolipoprotein E (ApoE)-knockout (KO) mice, and we analyze the role of autophagy in driving Tregs polarization. We observed defective maturation of Tregs from ApoE-KO mice in response to tumor growth factor-β (TGFβ). TGFβ is a well-known autophagy inducer, and Tregs maturation defects in ApoE-KO mice seem to be related to autophagy impairment. In this work, we propose that autophagy underlies Tregs maturation, advocating that the study of this process in atherosclerosis may open new therapeutic strategies.
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Affiliation(s)
- Sara Mandatori
- Unit of Histology and Medical Embryology, Department of Anatomy, Histology, Forensic Medicine and Orthopaedics, Sapienza University of Rome, Rome, Italy
| | - Ilenia Pacella
- Laboratory of Cellular and Molecular Immunology, Department of Internal Clinical Sciences, Anaesthesiology and Cardiovascular Sciences, Sapienza Università di Roma, Rome, Italy.,Laboratory Affiliated to Istituto Pasteur Italia - Fondazione Cenci Bolognetti, Rome, Italy
| | - Vincenzo Marzolla
- Laboratory of Cardiovascular Endocrinology, IRCCS San Raffaele Pisana, Rome, Italy
| | - Caterina Mammi
- Laboratory of Cardiovascular Endocrinology, IRCCS San Raffaele Pisana, Rome, Italy
| | - Donatella Starace
- UOC, Clinical Pathology, San Giovanni Addolorata Hospital, Rome, Italy
| | - Fabrizio Padula
- Unit of Histology and Medical Embryology, Department of Anatomy, Histology, Forensic Medicine and Orthopaedics, Sapienza University of Rome, Rome, Italy
| | - Laura Vitiello
- Flow Cytometry Unit, IRCCS San Raffaele Pisana, Rome, Italy
| | - Andrea Armani
- Laboratory of Cardiovascular Endocrinology, IRCCS San Raffaele Pisana, Rome, Italy
| | - Carmine Savoia
- Cardiology Unit, Department of Clinical and Molecular Medicine, Sant'Andrea Hospital, Sapienza University of Rome, Rome, Italy
| | - Maurizio Taurino
- Unit of Vascular Surgery, Department of Clinical and Molecular Medicine, Sant'Andrea Hospital, Sapienza University of Rome, Rome, Italy
| | - Daniela De Zio
- Cell Stress and Survival Unit, Center of Autophagy, Recycling and Disease (CARD), Danish Cancer Society Research Center, Copenhagen, Denmark
| | - Claudia Giampietri
- Unit of Human Anatomy, Department of Anatomy, Histology, Forensic Medicine and Orthopaedics, Sapienza University of Rome, Rome, Italy
| | - Silvia Piconese
- Laboratory of Cellular and Molecular Immunology, Department of Internal Clinical Sciences, Anaesthesiology and Cardiovascular Sciences, Sapienza Università di Roma, Rome, Italy.,Laboratory Affiliated to Istituto Pasteur Italia - Fondazione Cenci Bolognetti, Rome, Italy
| | - Francesco Cecconi
- Cell Stress and Survival Unit, Center of Autophagy, Recycling and Disease (CARD), Danish Cancer Society Research Center, Copenhagen, Denmark.,Department of Paediatric Haematology and Oncology, IRCCS Bambino Gesù Children's Hospital, Rome, Italy.,Department of Biology, University of Rome Tor Vergata, Rome, Italy
| | - Massimiliano Caprio
- Laboratory of Cardiovascular Endocrinology, IRCCS San Raffaele Pisana, Rome, Italy.,Department of Human Sciences and Promotion of the Quality of Life, San Raffaele Roma Open University, Rome, Italy
| | - Antonio Filippini
- Unit of Histology and Medical Embryology, Department of Anatomy, Histology, Forensic Medicine and Orthopaedics, Sapienza University of Rome, Rome, Italy
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24
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Fu Y, Lin Q, Zhang Z, Zhang L. Therapeutic strategies for the costimulatory molecule OX40 in T-cell-mediated immunity. Acta Pharm Sin B 2020; 10:414-433. [PMID: 32140389 PMCID: PMC7049610 DOI: 10.1016/j.apsb.2019.08.010] [Citation(s) in RCA: 171] [Impact Index Per Article: 34.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2019] [Revised: 07/18/2019] [Accepted: 07/19/2019] [Indexed: 12/11/2022] Open
Abstract
The T cell co-stimulatory molecule OX40 and its cognate ligand OX40L have attracted broad research interest as a therapeutic target in T cell-mediated diseases. Accumulating preclinical evidence highlights the therapeutic efficacy of both agonist and blockade of the OX40-OX40L interaction. Despite this progress, many questions about the immuno-modulator roles of OX40 on T cell function remain unanswered. In this review we summarize the impact of the OX40-OX40L interaction on T cell subsets, including Th1, Th2, Th9, Th17, Th22, Treg, Tfh, and CD8+ T cells, to gain a comprehensive understanding of anti-OX40 mAb-based therapies. The potential therapeutic application of the OX40-OX40L interaction in autoimmunity diseases and cancer immunotherapy are further discussed; OX40-OX40L blockade may ameliorate autoantigen-specific T cell responses and reduce immune activity in autoimmunity diseases. We also explore the rationale of targeting OX40-OX40L interactions in cancer immunotherapy. Ligation of OX40 with targeted agonist anti-OX40 mAbs conveys activating signals to T cells. When combined with other therapeutic treatments, such as anti-PD-1 or anti-CTLA-4 blockade, cytokines, chemotherapy, or radiotherapy, the anti-tumor activity of agonist anti-OX40 treatment will be further enhanced. These data collectively suggest great potential for OX40-mediated therapies.
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Affiliation(s)
- Yu Fu
- Key Laboratory of Drug Targeting and Drug Delivery System of the Education Ministry, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, College of Polymer Science and Engineering, West China School of Pharmacy, Sichuan University, Chengdu 610064, China
- Department of Pharmacology, Yale University School of Medicine, New Haven, CT 06510, USA
| | - Qing Lin
- Key Laboratory of Drug Targeting and Drug Delivery System of the Education Ministry, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, College of Polymer Science and Engineering, West China School of Pharmacy, Sichuan University, Chengdu 610064, China
| | - Zhirong Zhang
- Key Laboratory of Drug Targeting and Drug Delivery System of the Education Ministry, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, College of Polymer Science and Engineering, West China School of Pharmacy, Sichuan University, Chengdu 610064, China
| | - Ling Zhang
- Key Laboratory of Drug Targeting and Drug Delivery System of the Education Ministry, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, College of Polymer Science and Engineering, West China School of Pharmacy, Sichuan University, Chengdu 610064, China
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25
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Sun Y, Luo J, Chen Y, Cui J, Lei Y, Cui Y, Jiang N, Jiang W, Chen L, Chen Y, Kuang Y, Tang K, Ke Z. Combined evaluation of the expression status of CD155 and TIGIT plays an important role in the prognosis of LUAD (lung adenocarcinoma). Int Immunopharmacol 2020; 80:106198. [PMID: 31954274 DOI: 10.1016/j.intimp.2020.106198] [Citation(s) in RCA: 74] [Impact Index Per Article: 14.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2019] [Revised: 12/13/2019] [Accepted: 01/06/2020] [Indexed: 12/25/2022]
Abstract
The interaction between CD155 and its high-affinity ligand TIGIT is being increasingly investigated in various solid tumors. However, the prognostic significance of CD155 and TIGIT in lung adenocarcinoma (LUAD) remains unclear. In this study, immunohistochemistry was applied in 334 LUAD cases to evaluate the expression of CD155 and TIGIT. Western blotting was conducted in 5 paired primary LUAD and adjacent normal lung tissues. Our results reveal that CD155 and TIGIT are overexpressed in LUAD tissues and that aberrant overexpression is closely correlated with poor clinical outcomes (P < 0.01). The multivariate model also shows that CD155 expression is an independent risk factor for LUAD (RR, 1.34; P = 0.036). Moreover, patients expressing high CD155 and TIGIT simultaneously presented shorter overall survival (OS) (P < 0.01) and progression-free survival (PFS) (P < 0.01). These findings suggest that CD155 and TIGIT can make up a prognosticating tool to predict clinical outcomes, thereby contributing to personalized medical care in LUAD.
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Affiliation(s)
- Yu Sun
- Department of Pathology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510080, PR China
| | - Jiping Luo
- Department of Pathology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510080, PR China
| | - Yangshan Chen
- Department of Pathology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510080, PR China
| | - Ji Cui
- Gastrointestinal Surgery Center, First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510080, PR China
| | - Yiyan Lei
- Department of Thoracic Surgery, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510080, PR China
| | - Yongmei Cui
- Department of Pathology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510080, PR China
| | - Neng Jiang
- Department of Pathology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510080, PR China
| | - Wenting Jiang
- Department of Pathology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510080, PR China
| | - Lili Chen
- Department of Pathology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510080, PR China
| | - Yanyang Chen
- Department of Pathology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510080, PR China
| | - Yukun Kuang
- Department of Respiratory Medicine, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510080, PR China
| | - Kejing Tang
- Department of Respiratory Medicine, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510080, PR China
| | - Zunfu Ke
- Department of Pathology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510080, PR China; Institute of Precision Medicine, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, Guangdong 510080, PR China.
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26
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Odobasic D, Ruth AJ, Oudin V, Kitching AR, Holdsworth SR. OX40 ligand is inhibitory during the effector phase of crescentic glomerulonephritis. Nephrol Dial Transplant 2019; 34:429-441. [PMID: 29939347 DOI: 10.1093/ndt/gfy177] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2018] [Accepted: 05/15/2018] [Indexed: 01/09/2023] Open
Abstract
BACKGROUND The functional relevance of OX40 ligand (OX40L) in the effector phase of crescentic glomerulonephritis (GN) is unknown. These studies defined the role of endogenous OX40L during the effector stage of murine crescentic GN. METHODS GN was induced by immunization with sheep globulin/adjuvant on Day 0 and injection of sheep anti-mouse glomerular basement membrane immunoglobulin (Ig) on Day 10. Rat IgG or neutralizing anti-OX40L antibody was administered on Days 10-18 and immune responses and renal injury assessed on Day 20. RESULTS Compared with naïve animals, OX40L was upregulated in the lymph nodes (LNs) and on leucocytes and resident non-immune cells in the kidneys of mice with GN. Inhibition of OX40L in GN augmented renal injury, as indicated by increased crescent formation, proteinuria and glomerular leucocyte accumulation. In line with increased injury, anti-OX40L treatment increased proliferation and decreased apoptosis of CD4 T cells in the LNs, without affecting LN CD4 cytokine production and CD8 T-cell responses. Blockade of OX40L decreased LN regulatory T-cell (Treg) proliferation, transforming growth factor β production and foxp3 expression. OX40L inhibition did not affect B cell expansion or circulating antibody levels. In the kidney, neutralization of OX40L augmented interferon γ (IFNγ) expression by CD4 and CD8 T cells and shifted macrophage polarization towards the pro-inflammatory M1 phenotype. CONCLUSIONS OX40L is protective during the effector phase of murine crescentic GN by reducing the expansion of CD4 T cells and enhancing Treg responses in the LNs, and by locally inhibiting T-cell IFNγ production and pro-inflammatory macrophage phenotype in the kidney.
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Affiliation(s)
- Dragana Odobasic
- Centre for Inflammatory Diseases, Department of Medicine, Monash University, Monash Medical Centre, Clayton, Victoria, Australia
| | - Amanda J Ruth
- Centre for Inflammatory Diseases, Department of Medicine, Monash University, Monash Medical Centre, Clayton, Victoria, Australia
| | - Virginie Oudin
- Centre for Inflammatory Diseases, Department of Medicine, Monash University, Monash Medical Centre, Clayton, Victoria, Australia
| | - A Richard Kitching
- Centre for Inflammatory Diseases, Department of Medicine, Monash University, Monash Medical Centre, Clayton, Victoria, Australia.,Department of Pediatric Nephrology, Monash Health, Clayton, Victoria, Australia.,Department of Nephrology, Monash Health, Clayton, Victoria, Australia
| | - Stephen R Holdsworth
- Centre for Inflammatory Diseases, Department of Medicine, Monash University, Monash Medical Centre, Clayton, Victoria, Australia.,Department of Nephrology, Monash Health, Clayton, Victoria, Australia
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27
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Immune checkpoint molecules. Possible future therapeutic implications in autoimmune diseases. J Autoimmun 2019; 104:102333. [DOI: 10.1016/j.jaut.2019.102333] [Citation(s) in RCA: 64] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2019] [Accepted: 08/29/2019] [Indexed: 02/07/2023]
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28
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Cossarizza A, Chang HD, Radbruch A, Acs A, Adam D, Adam-Klages S, Agace WW, Aghaeepour N, Akdis M, Allez M, Almeida LN, Alvisi G, Anderson G, Andrä I, Annunziato F, Anselmo A, Bacher P, Baldari CT, Bari S, Barnaba V, Barros-Martins J, Battistini L, Bauer W, Baumgart S, Baumgarth N, Baumjohann D, Baying B, Bebawy M, Becher B, Beisker W, Benes V, Beyaert R, Blanco A, Boardman DA, Bogdan C, Borger JG, Borsellino G, Boulais PE, Bradford JA, Brenner D, Brinkman RR, Brooks AES, Busch DH, Büscher M, Bushnell TP, Calzetti F, Cameron G, Cammarata I, Cao X, Cardell SL, Casola S, Cassatella MA, Cavani A, Celada A, Chatenoud L, Chattopadhyay PK, Chow S, Christakou E, Čičin-Šain L, Clerici M, Colombo FS, Cook L, Cooke A, Cooper AM, Corbett AJ, Cosma A, Cosmi L, Coulie PG, Cumano A, Cvetkovic L, Dang VD, Dang-Heine C, Davey MS, Davies D, De Biasi S, Del Zotto G, Cruz GVD, Delacher M, Bella SD, Dellabona P, Deniz G, Dessing M, Di Santo JP, Diefenbach A, Dieli F, Dolf A, Dörner T, Dress RJ, Dudziak D, Dustin M, Dutertre CA, Ebner F, Eckle SBG, Edinger M, Eede P, Ehrhardt GR, Eich M, Engel P, Engelhardt B, Erdei A, et alCossarizza A, Chang HD, Radbruch A, Acs A, Adam D, Adam-Klages S, Agace WW, Aghaeepour N, Akdis M, Allez M, Almeida LN, Alvisi G, Anderson G, Andrä I, Annunziato F, Anselmo A, Bacher P, Baldari CT, Bari S, Barnaba V, Barros-Martins J, Battistini L, Bauer W, Baumgart S, Baumgarth N, Baumjohann D, Baying B, Bebawy M, Becher B, Beisker W, Benes V, Beyaert R, Blanco A, Boardman DA, Bogdan C, Borger JG, Borsellino G, Boulais PE, Bradford JA, Brenner D, Brinkman RR, Brooks AES, Busch DH, Büscher M, Bushnell TP, Calzetti F, Cameron G, Cammarata I, Cao X, Cardell SL, Casola S, Cassatella MA, Cavani A, Celada A, Chatenoud L, Chattopadhyay PK, Chow S, Christakou E, Čičin-Šain L, Clerici M, Colombo FS, Cook L, Cooke A, Cooper AM, Corbett AJ, Cosma A, Cosmi L, Coulie PG, Cumano A, Cvetkovic L, Dang VD, Dang-Heine C, Davey MS, Davies D, De Biasi S, Del Zotto G, Cruz GVD, Delacher M, Bella SD, Dellabona P, Deniz G, Dessing M, Di Santo JP, Diefenbach A, Dieli F, Dolf A, Dörner T, Dress RJ, Dudziak D, Dustin M, Dutertre CA, Ebner F, Eckle SBG, Edinger M, Eede P, Ehrhardt GR, Eich M, Engel P, Engelhardt B, Erdei A, Esser C, Everts B, Evrard M, Falk CS, Fehniger TA, Felipo-Benavent M, Ferry H, Feuerer M, Filby A, Filkor K, Fillatreau S, Follo M, Förster I, Foster J, Foulds GA, Frehse B, Frenette PS, Frischbutter S, Fritzsche W, Galbraith DW, Gangaev A, Garbi N, Gaudilliere B, Gazzinelli RT, Geginat J, Gerner W, Gherardin NA, Ghoreschi K, Gibellini L, Ginhoux F, Goda K, Godfrey DI, Goettlinger C, González-Navajas JM, Goodyear CS, Gori A, Grogan JL, Grummitt D, Grützkau A, Haftmann C, Hahn J, Hammad H, Hämmerling G, Hansmann L, Hansson G, Harpur CM, Hartmann S, Hauser A, Hauser AE, Haviland DL, Hedley D, Hernández DC, Herrera G, Herrmann M, Hess C, Höfer T, Hoffmann P, Hogquist K, Holland T, Höllt T, Holmdahl R, Hombrink P, Houston JP, Hoyer BF, Huang B, Huang FP, Huber JE, Huehn J, Hundemer M, Hunter CA, Hwang WYK, Iannone A, Ingelfinger F, Ivison SM, Jäck HM, Jani PK, Jávega B, Jonjic S, Kaiser T, Kalina T, Kamradt T, Kaufmann SHE, Keller B, Ketelaars SLC, Khalilnezhad A, Khan S, Kisielow J, Klenerman P, Knopf J, Koay HF, Kobow K, Kolls JK, Kong WT, Kopf M, Korn T, Kriegsmann K, Kristyanto H, Kroneis T, Krueger A, Kühne J, Kukat C, Kunkel D, Kunze-Schumacher H, Kurosaki T, Kurts C, Kvistborg P, Kwok I, Landry J, Lantz O, Lanuti P, LaRosa F, Lehuen A, LeibundGut-Landmann S, Leipold MD, Leung LY, Levings MK, Lino AC, Liotta F, Litwin V, Liu Y, Ljunggren HG, Lohoff M, Lombardi G, Lopez L, López-Botet M, Lovett-Racke AE, Lubberts E, Luche H, Ludewig B, Lugli E, Lunemann S, Maecker HT, Maggi L, Maguire O, Mair F, Mair KH, Mantovani A, Manz RA, Marshall AJ, Martínez-Romero A, Martrus G, Marventano I, Maslinski W, Matarese G, Mattioli AV, Maueröder C, Mazzoni A, McCluskey J, McGrath M, McGuire HM, McInnes IB, Mei HE, Melchers F, Melzer S, Mielenz D, Miller SD, Mills KH, Minderman H, Mjösberg J, Moore J, Moran B, Moretta L, Mosmann TR, Müller S, Multhoff G, Muñoz LE, Münz C, Nakayama T, Nasi M, Neumann K, Ng LG, Niedobitek A, Nourshargh S, Núñez G, O’Connor JE, Ochel A, Oja A, Ordonez D, Orfao A, Orlowski-Oliver E, Ouyang W, Oxenius A, Palankar R, Panse I, Pattanapanyasat K, Paulsen M, Pavlinic D, Penter L, Peterson P, Peth C, Petriz J, Piancone F, Pickl WF, Piconese S, Pinti M, Pockley AG, Podolska MJ, Poon Z, Pracht K, Prinz I, Pucillo CEM, Quataert SA, Quatrini L, Quinn KM, Radbruch H, Radstake TRDJ, Rahmig S, Rahn HP, Rajwa B, Ravichandran G, Raz Y, Rebhahn JA, Recktenwald D, Reimer D, e Sousa CR, Remmerswaal EB, Richter L, Rico LG, Riddell A, Rieger AM, Robinson JP, Romagnani C, Rubartelli A, Ruland J, Saalmüller A, Saeys Y, Saito T, Sakaguchi S, de-Oyanguren FS, Samstag Y, Sanderson S, Sandrock I, Santoni A, Sanz RB, Saresella M, Sautes-Fridman C, Sawitzki B, Schadt L, Scheffold A, Scherer HU, Schiemann M, Schildberg FA, Schimisky E, Schlitzer A, Schlosser J, Schmid S, Schmitt S, Schober K, Schraivogel D, Schuh W, Schüler T, Schulte R, Schulz AR, Schulz SR, Scottá C, Scott-Algara D, Sester DP, Shankey TV, Silva-Santos B, Simon AK, Sitnik KM, Sozzani S, Speiser DE, Spidlen J, Stahlberg A, Stall AM, Stanley N, Stark R, Stehle C, Steinmetz T, Stockinger H, Takahama Y, Takeda K, Tan L, Tárnok A, Tiegs G, Toldi G, Tornack J, Traggiai E, Trebak M, Tree TI, Trotter J, Trowsdale J, Tsoumakidou M, Ulrich H, Urbanczyk S, van de Veen W, van den Broek M, van der Pol E, Van Gassen S, Van Isterdael G, van Lier RA, Veldhoen M, Vento-Asturias S, Vieira P, Voehringer D, Volk HD, von Borstel A, von Volkmann K, Waisman A, Walker RV, Wallace PK, Wang SA, Wang XM, Ward MD, Ward-Hartstonge KA, Warnatz K, Warnes G, Warth S, Waskow C, Watson JV, Watzl C, Wegener L, Weisenburger T, Wiedemann A, Wienands J, Wilharm A, Wilkinson RJ, Willimsky G, Wing JB, Winkelmann R, Winkler TH, Wirz OF, Wong A, Wurst P, Yang JHM, Yang J, Yazdanbakhsh M, Yu L, Yue A, Zhang H, Zhao Y, Ziegler SM, Zielinski C, Zimmermann J, Zychlinsky A. Guidelines for the use of flow cytometry and cell sorting in immunological studies (second edition). Eur J Immunol 2019; 49:1457-1973. [PMID: 31633216 PMCID: PMC7350392 DOI: 10.1002/eji.201970107] [Show More Authors] [Citation(s) in RCA: 743] [Impact Index Per Article: 123.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
These guidelines are a consensus work of a considerable number of members of the immunology and flow cytometry community. They provide the theory and key practical aspects of flow cytometry enabling immunologists to avoid the common errors that often undermine immunological data. Notably, there are comprehensive sections of all major immune cell types with helpful Tables detailing phenotypes in murine and human cells. The latest flow cytometry techniques and applications are also described, featuring examples of the data that can be generated and, importantly, how the data can be analysed. Furthermore, there are sections detailing tips, tricks and pitfalls to avoid, all written and peer-reviewed by leading experts in the field, making this an essential research companion.
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Affiliation(s)
- Andrea Cossarizza
- Department of Medical and Surgical Sciences for Children and Adults, Univ. of Modena and Reggio Emilia School of Medicine, Modena, Italy
| | - Hyun-Dong Chang
- Deutsches Rheuma-Forschungszentrum (DRFZ), an Institute of the Leibniz Association, Berlin, Germany
| | - Andreas Radbruch
- Deutsches Rheuma-Forschungszentrum (DRFZ), an Institute of the Leibniz Association, Berlin, Germany
| | - Andreas Acs
- Department of Biology, Nikolaus-Fiebiger-Center for Molecular Medicine, Friedrich-Alexander-University Erlangen-Nuremberg, Erlangen, Germany
| | - Dieter Adam
- Institut für Immunologie, Christian-Albrechts-Universität zu Kiel, Kiel, Germany
| | - Sabine Adam-Klages
- Institut für Transfusionsmedizin, Universitätsklinik Schleswig-Holstein, Kiel, Germany
| | - William W. Agace
- Mucosal Immunology group, Department of Health Technology, Technical University of Denmark, Kgs. Lyngby, Denmark
- Immunology Section, Lund University, Lund, Sweden
| | - Nima Aghaeepour
- Departments of Anesthesiology, Pain and Perioperative Medicine; Biomedical Data Sciences; and Pediatrics, Stanford University, Stanford, CA, USA
| | - Mübeccel Akdis
- Swiss Institute of Allergy and Asthma Research (SIAF), University of Zurich, Davos, Switzerland
| | - Matthieu Allez
- Université de Paris, Institut de Recherche Saint-Louis, INSERM U1160, and Gastroenterology Department, Hôpital Saint-Louis – APHP, Paris, France
| | | | - Giorgia Alvisi
- Laboratory of Translational Immunology, Humanitas Clinical and Research Center, Rozzano, Italy
| | | | - Immanuel Andrä
- Institut für Medizinische Mikrobiologie, Immunologie und Hygiene, Technische Universität München, Munich, Germany
| | - Francesco Annunziato
- Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy
| | - Achille Anselmo
- Flow Cytometry Core, Humanitas Clinical and Research Center, Milan, Italy
| | - Petra Bacher
- Institut für Immunologie, Christian-Albrechts-Universität zu Kiel, Kiel, Germany
- Institut für Klinische Molekularbiologie, Christian-Albrechts Universität zu Kiel, Germany
| | | | - Sudipto Bari
- Division of Medical Sciences, National Cancer Centre Singapore, Singapore
- Cancer & Stem Cell Biology, Duke-NUS Medical School, Singapore
| | - Vincenzo Barnaba
- Dipartimento di Medicina Interna e Specialità Mediche, Sapienza Università di Roma, Rome, Italy
- Center for Life Nano Science@Sapienza, Istituto Italiano di Tecnologia, Rome, Italy
- Istituto Pasteur - Fondazione Cenci Bolognetti, Rome, Italy
| | | | | | - Wolfgang Bauer
- Division of Immunology, Allergy and Infectious Diseases, Department of Dermatology, Medical University of Vienna, Vienna, Austria
| | - Sabine Baumgart
- Deutsches Rheuma-Forschungszentrum (DRFZ), an Institute of the Leibniz Association, Berlin, Germany
| | - Nicole Baumgarth
- Center for Comparative Medicine & Dept. Pathology, Microbiology & Immunology, University of California, Davis, CA, USA
| | - Dirk Baumjohann
- Institute for Immunology, Faculty of Medicine, Biomedical Center, LMU Munich, Planegg-Martinsried, Germany
| | - Bianka Baying
- Genomics Core Facility, European Molecular Biology Laboratory (EMBL), Heidelberg, Germany
| | - Mary Bebawy
- Discipline of Pharmacy, Graduate School of Health, The University of Technology Sydney, Sydney, NSW, Australia
| | - Burkhard Becher
- Institute of Experimental Immunology, University of Zurich, Zurich, Switzerland
- Comprehensive Cancer Center Zurich, Switzerland
| | - Wolfgang Beisker
- Flow Cytometry Laboratory, Institute of Molecular Toxicology and Pharmacology, Helmholtz Zentrum München, German Research Center for Environmental Health, München, Germany
| | - Vladimir Benes
- Genomics Core Facility, European Molecular Biology Laboratory (EMBL), Heidelberg, Germany
| | - Rudi Beyaert
- Department of Biomedical Molecular Biology, Center for Inflammation Research, Ghent University - VIB, Ghent, Belgium
| | - Alfonso Blanco
- Flow Cytometry Core Technologies, UCD Conway Institute, University College Dublin, Dublin, Ireland
| | - Dominic A. Boardman
- Department of Surgery, The University of British Columbia, Vancouver, Canada
- BC Children’s Hospital Research Institute, Vancouver, Canada
| | - Christian Bogdan
- Mikrobiologisches Institut - Klinische Mikrobiologie, Immunologie und Hygiene, Universitätsklinikum Erlangen, Erlangen, Germany
- Friedrich-Alexander-Universität (FAU) Erlangen-Nürnberg and Medical Immunology Campus Erlangen, Erlangen, Germany
| | - Jessica G. Borger
- Department of Immunology and Pathology, Monash University, Melbourne, Victoria, Australia
| | - Giovanna Borsellino
- Neuroimmunology and Flow Cytometry Units, Fondazione Santa Lucia IRCCS, Rome, Italy
| | - Philip E. Boulais
- Department of Cell Biology, Albert Einstein College of Medicine, Bronx, NY, USA
- The Ruth L. and David S. Gottesman Institute for Stem Cell and Regenerative Medicine Research, Bronx, New York, USA
| | | | - Dirk Brenner
- Luxembourg Institute of Health, Department of Infection and Immunity, Experimental and Molecular Immunology, Esch-sur-Alzette, Luxembourg
- Odense University Hospital, Odense Research Center for Anaphylaxis, University of Southern Denmark, Department of Dermatology and Allergy Center, Odense, Denmark
- Luxembourg Centre for Systems Biomedicine (LCSB), University of Luxembourg, Belvaux, Luxembourg
| | - Ryan R. Brinkman
- Department of Medical Genetics, University of British Columbia, Vancouver, BC, Canada
- Terry Fox Laboratory, BC Cancer, Vancouver, BC, Canada
| | - Anna E. S. Brooks
- University of Auckland, School of Biological Sciences, Maurice Wilkins Center, Auckland, New Zealand
| | - Dirk H. Busch
- Institut für Medizinische Mikrobiologie, Immunologie und Hygiene, Technische Universität München, Munich, Germany
- German Center for Infection Research (DZIF), Munich, Germany
- Focus Group “Clinical Cell Processing and Purification”, Institute for Advanced Study, Technische Universität München, Munich, Germany
| | - Martin Büscher
- Biophysics, R&D Engineering, Miltenyi Biotec GmbH, Bergisch Gladbach, Germany
| | - Timothy P. Bushnell
- Department of Pediatrics and Shared Resource Laboratories, University of Rochester Medical Center, Rochester, NY, USA
| | - Federica Calzetti
- University of Verona, Department of Medicine, Section of General Pathology, Verona, Italy
| | - Garth Cameron
- Department of Microbiology and Immunology, Peter Doherty Institute for Infection and Immunity, University of Melbourne, Parkville, Victoria, Australia
| | - Ilenia Cammarata
- Dipartimento di Medicina Interna e Specialità Mediche, Sapienza Università di Roma, Rome, Italy
| | - Xuetao Cao
- National Key Laboratory of Medical Immunology, Nankai University, Tianjin, China
| | - Susanna L. Cardell
- Department of Microbiology and Immunology, University of Gothenburg, Gothenburg, Sweden
| | - Stefano Casola
- The FIRC Institute of Molecular Oncology (FOM), Milan, Italy
| | - Marco A. Cassatella
- University of Verona, Department of Medicine, Section of General Pathology, Verona, Italy
| | - Andrea Cavani
- National Institute for Health, Migration and Poverty (INMP), Rome, Italy
| | - Antonio Celada
- Macrophage Biology Group, School of Biology, University of Barcelona, Barcelona, Spain
| | - Lucienne Chatenoud
- Université Paris Descartes, Institut National de la Santé et de la Recherche Médicale, Paris, France
| | | | - Sue Chow
- Divsion of Medical Oncology and Hematology, Princess Margaret Hospital, Toronto, Ontario, Canada
| | - Eleni Christakou
- Department of Immunobiology, School of Immunology and Microbial Sciences, King’s College London, UK
- National Institutes of Health Research Biomedical Research Centre at Guy’s and St. Thomas’ National Health Service, Foundation Trust and King’s College London, UK
| | - Luka Čičin-Šain
- Department of Vaccinology and Applied Microbiology, Helmholtz Centre for Infection Research, Braunschweig, Germany
| | - Mario Clerici
- IRCCS Fondazione Don Carlo Gnocchi, Milan, Italy
- Department of Physiopathology and Transplants, University of Milan, Milan, Italy
- Milan Center for Neuroscience, University of Milano-Bicocca, Milan, Italy
| | | | - Laura Cook
- BC Children’s Hospital Research Institute, Vancouver, Canada
- Department of Medicine, The University of British Columbia, Vancouver, Canada
| | - Anne Cooke
- Department of Pathology, University of Cambridge, Cambridge, UK
| | - Andrea M. Cooper
- Department of Respiratory Sciences, University of Leicester, Leicester, UK
| | - Alexandra J. Corbett
- Department of Microbiology and Immunology, Peter Doherty Institute for Infection and Immunity, University of Melbourne, Parkville, Victoria, Australia
| | - Antonio Cosma
- National Cytometry Platform, Luxembourg Institute of Health, Department of Infection and Immunity, Esch-sur-Alzette, Luxembourg
| | - Lorenzo Cosmi
- Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy
| | - Pierre G. Coulie
- de Duve Institute, Université catholique de Louvain, Brussels, Belgium
| | - Ana Cumano
- Unit Lymphopoiesis, Department of Immunology, Institut Pasteur, Paris, France
| | - Ljiljana Cvetkovic
- Division of Molecular Immunology, Nikolaus-Fiebiger-Center, Dept. of Internal Medicine III, University of Erlangen-Nuremberg, Erlangen, Germany
| | - Van Duc Dang
- Deutsches Rheuma-Forschungszentrum (DRFZ), an Institute of the Leibniz Association, Berlin, Germany
| | - Chantip Dang-Heine
- Clinical Research Unit, Berlin Institute of Health (BIH), Charite Universitätsmedizin Berlin, Berlin, Germany
| | - Martin S. Davey
- Infection and Immunity Program and Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Clayton, Victoria, Australia
- Australian Research Council Centre of Excellence in Advanced Molecular Imaging, Monash University, Clayton, Victoria, Australia
| | - Derek Davies
- Flow Cytometry Scientific Technology Platform, The Francis Crick Institute, London, UK
| | - Sara De Biasi
- Department of Surgery, Medicine, Dentistry and Morphological Sciences, Univ. of Modena and Reggio Emilia, Modena, Italy
| | | | - Gelo Victoriano Dela Cruz
- Novo Nordisk Foundation Center for Stem Cell Biology – DanStem, University of Copenhagen, Copenhagen, Denmark
| | - Michael Delacher
- Regensburg Center for Interventional Immunology (RCI), Regensburg, Germany
- Chair for Immunology, University Regensburg, Germany
| | - Silvia Della Bella
- Department of Medical Biotechnologies and Translational Medicine, University of Milan, Milan, Italy
| | - Paolo Dellabona
- Division of Immunology, Transplantation and Infectious Diseases, San Raffaele Scientific Institute, Milan, Italy
| | - Günnur Deniz
- Istanbul University, Aziz Sancar Institute of Experimental Medicine, Department of Immunology, Istanbul, Turkey
| | | | - James P. Di Santo
- Innate Immunty Unit, Department of Immunology, Institut Pasteur, Paris, France
- Institut Pasteur, Inserm U1223, Paris, France
| | - Andreas Diefenbach
- Deutsches Rheuma-Forschungszentrum (DRFZ), an Institute of the Leibniz Association, Berlin, Germany
- Charité - Universitätsmedizin Berlin, Laboratory of Innate Immunity, Department of Microbiology, Infectious Diseases and Immunology, Berlin, Germany
- Berlin Institute of Health (BIH), Berlin, Germany
| | - Francesco Dieli
- University of Palermo, Central Laboratory of Advanced Diagnosis and Biomedical Research, Department of Biomedicine, Neurosciences and Advanced Diagnostics, Palermo, Italy
| | - Andreas Dolf
- Flow Cytometry Core Facility, Institute of Experimental Immunology, University of Bonn, Bonn, Germany
| | - Thomas Dörner
- Deutsches Rheuma-Forschungszentrum (DRFZ), an Institute of the Leibniz Association, Berlin, Germany
- Dept. Medicine/Rheumatology and Clinical Immunology, Charité Universitätsmedizin Berlin, Germany
| | - Regine J. Dress
- Singapore Immunology Network (SIgN), A*STAR (Agency for Science, Technology and Research), Biopolis, Singapore
| | - Diana Dudziak
- Department of Dermatology, Laboratory of Dendritic Cell Biology, Friedrich-Alexander Universität Erlangen-Nürnberg (FAU), University Hospital Erlangen, Erlangen, Germany
| | - Michael Dustin
- Kennedy Institute of Rheumatology, University of Oxford, Oxford, UK
| | - Charles-Antoine Dutertre
- Program in Emerging Infectious Disease, Duke-NUS Medical School, Singapore
- Singapore Immunology Network (SIgN), A*STAR (Agency for Science, Technology and Research), Biopolis, Singapore
| | - Friederike Ebner
- Institute of Immunology, Centre for Infection Medicine, Department of Veterinary Medicine, Freie Universität Berlin, Germany
| | - Sidonia B. G. Eckle
- Department of Microbiology and Immunology, Peter Doherty Institute for Infection and Immunity, University of Melbourne, Parkville, Victoria, Australia
| | - Matthias Edinger
- Regensburg Center for Interventional Immunology (RCI), Regensburg, Germany
- Department of Internal Medicine III, University Hospital Regensburg, Germany
| | - Pascale Eede
- Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Department of Neuropathology, Germany
| | | | - Marcus Eich
- Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM gGmbH), Heidelberg, Germany
| | - Pablo Engel
- University of Barcelona, Faculty of Medicine and Health Sciences, Department of Biomedical Sciences, Barcelona, Spain
| | | | - Anna Erdei
- Department of Immunology, University L. Eotvos, Budapest, Hungary
| | - Charlotte Esser
- Leibniz Research Institute for Environmental Medicine, Düsseldorf, Germany
| | - Bart Everts
- Department of Parasitology, Leiden University Medical Center, Leiden, The Netherlands
| | - Maximilien Evrard
- Singapore Immunology Network (SIgN), A*STAR (Agency for Science, Technology and Research), Biopolis, Singapore
| | - Christine S. Falk
- Institute of Transplant Immunology, Hannover Medical School, MHH, Hannover, Germany
| | - Todd A. Fehniger
- Division of Oncology, Washington University School of Medicine, St. Louis, MO, USA
| | - Mar Felipo-Benavent
- Laboratory of Cytomics, Joint Research Unit CIPF-UVEG, Principe Felipe Research Center, Valencia, Spain
| | - Helen Ferry
- Experimental Medicine Division, Nuffield Department of Medicine, University of Oxford, Oxford, UK
| | - Markus Feuerer
- Regensburg Center for Interventional Immunology (RCI), Regensburg, Germany
- Chair for Immunology, University Regensburg, Germany
| | - Andrew Filby
- The Flow Cytometry Core Facility, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK
| | | | - Simon Fillatreau
- Institut Necker-Enfants Malades, Université Paris Descartes Sorbonne Paris Cité, Faculté de Médecine, AP-HP, Hôpital Necker Enfants Malades, INSERM U1151-CNRS UMR 8253, Paris, France
| | - Marie Follo
- Department of Medicine I, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
- Universitaetsklinikum FreiburgLighthouse Core Facility, Zentrum für Translationale Zellforschung, Klinik für Innere Medizin I, Freiburg, Germany
| | - Irmgard Förster
- Immunology and Environment, LIMES Institute, University of Bonn, Bonn, Germany
| | | | - Gemma A. Foulds
- John van Geest Cancer Research Centre, Nottingham Trent University, Nottingham, UK
| | - Britta Frehse
- Institute for Systemic Inflammation Research, University of Luebeck, Luebeck, Germany
| | - Paul S. Frenette
- Department of Cell Biology, Albert Einstein College of Medicine, Bronx, NY, USA
- The Ruth L. and David S. Gottesman Institute for Stem Cell and Regenerative Medicine Research, Bronx, New York, USA
- Department of Medicine, Albert Einstein College of Medicine, Bronx, NY, USA
| | - Stefan Frischbutter
- Deutsches Rheuma-Forschungszentrum (DRFZ), an Institute of the Leibniz Association, Berlin, Germany
- Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Department of Dermatology, Venereology and Allergology
| | - Wolfgang Fritzsche
- Nanobiophotonics Department, Leibniz Institute of Photonic Technology (IPHT), Jena, Germany
| | - David W. Galbraith
- School of Plant Sciences and Bio5 Institute, University of Arizona, Tucson, USA
- Honorary Dean of Life Sciences, Henan University, Kaifeng, China
| | - Anastasia Gangaev
- Division of Molecular Oncology and Immunology, the Netherlands Cancer Institute, Amsterdam, The Netherlands
| | - Natalio Garbi
- Institute of Experimental Immunology, University of Bonn, Germany
| | - Brice Gaudilliere
- Stanford Department of Anesthesiology, Perioperative and Pain Medicine, Stanford University School of Medicine, CA, USA
| | - Ricardo T. Gazzinelli
- Fundação Oswaldo Cruz - Minas, Laboratory of Immunopatology, Belo Horizonte, MG, Brazil
- Department of Mecicine, University of Massachusetts Medical School, Worcester, MA, USA
| | - Jens Geginat
- INGM - Fondazione Istituto Nazionale di Genetica Molecolare “Ronmeo ed Enrica Invernizzi”, Milan, Italy
| | - Wilhelm Gerner
- Institute of Immunology, Department of Pathobiology, University of Veterinary Medicine Vienna, Austria
- Christian Doppler Laboratory for Optimized Prediction of Vaccination Success in Pigs, Institute of Immunology, Department of Pathobiology, University of Veterinary Medicine Vienna, Austria
| | - Nicholas A. Gherardin
- Department of Microbiology and Immunology, Peter Doherty Institute for Infection and Immunity, University of Melbourne, Parkville, Victoria, Australia
| | - Kamran Ghoreschi
- Department of Dermatology, Venereology and Allergology, Charité - Universitätsmedizin Berlin, Berlin, Germany
| | - Lara Gibellini
- Department of Surgery, Medicine, Dentistry and Morphological Sciences, Univ. of Modena and Reggio Emilia, Modena, Italy
| | - Florent Ginhoux
- Singapore Immunology Network (SIgN), A*STAR (Agency for Science, Technology and Research), Biopolis, Singapore
- Translational Immunology Institute, SingHealth Duke-NUS Academic Medical Centre, Singapore
- Shanghai Institute of Immunology, Department of Immunology and Microbiology, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Keisuke Goda
- Department of Bioengineering, University of California, Los Angeles, California, USA
- Department of Chemistry, University of Tokyo, Tokyo, Japan
- Institute of Technological Sciences, Wuhan University, Wuhan, China
| | - Dale I. Godfrey
- Department of Microbiology and Immunology, Peter Doherty Institute for Infection and Immunity, University of Melbourne, Parkville, Victoria, Australia
| | | | - Jose M. González-Navajas
- Alicante Institute for Health and Biomedical Research (ISABIAL), Alicante, Spain
- Networked Biomedical Research Center for Hepatic and Digestive Diseases (CIBERehd), Madrid, Spain
| | - Carl S. Goodyear
- Institute of Infection Immunity and Inflammation, College of Medical Veterinary and Life Sciences, University of Glasgow, Glasgow Biomedical Research Centre, Glasgow, UK
| | - Andrea Gori
- Fondazione IRCCS Ca’ Granda, Ospedale Maggiore Policlinico, University of Milan
| | - Jane L. Grogan
- Cancer Immunology Research, Genentech, South San Francisco, CA, USA
| | | | - Andreas Grützkau
- Deutsches Rheuma-Forschungszentrum (DRFZ), an Institute of the Leibniz Association, Berlin, Germany
| | - Claudia Haftmann
- Institute of Experimental Immunology, University of Zurich, Zurich, Switzerland
| | - Jonas Hahn
- Friedrich-Alexander-University Erlangen-Nürnberg (FAU), Department of Medicine 3, Rheumatology and Immunology, Universitätsklinikum Erlangen, Erlangen
| | - Hamida Hammad
- Department of Internal Medicine and Pediatrics, Faculty of Medicine and Health Sciences, Zwijnaarde, Belgium
| | | | - Leo Hansmann
- Berlin Institute of Health (BIH), Berlin, Germany
- German Cancer Consortium (DKTK), partner site Berlin, Berlin, Germany
- Department of Hematology, Oncology, and Tumor Immunology, Charité - Universitätsmedizin Berlin, Campus Virchow Klinikum, Berlin, Germany
| | - Goran Hansson
- Department of Medicine and Center for Molecular Medicine at Karolinska University Hospital, Solna, Sweden
| | | | - Susanne Hartmann
- Institute of Immunology, Centre for Infection Medicine, Department of Veterinary Medicine, Freie Universität Berlin, Germany
| | - Andrea Hauser
- Department of Internal Medicine III, University Hospital Regensburg, Germany
| | - Anja E. Hauser
- Deutsches Rheuma-Forschungszentrum (DRFZ), an Institute of the Leibniz Association, Berlin, Germany
- Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin
- Department of Rheumatology and Clinical Immunology, Berlin Institute of Health, Berlin, Germany
| | - David L. Haviland
- Flow Cytometry, Houston Methodist Hospital Research Institute, Houston, TX, USA
| | - David Hedley
- Divsion of Medical Oncology and Hematology, Princess Margaret Hospital, Toronto, Ontario, Canada
| | - Daniela C. Hernández
- Deutsches Rheuma-Forschungszentrum (DRFZ), an Institute of the Leibniz Association, Berlin, Germany
- Charité - Universitätsmedizin Berlin, Medical Department I, Division of Gastroenterology, Infectiology and Rheumatology, Berlin, Germany
| | - Guadalupe Herrera
- Cytometry Service, Incliva Foundation. Clinic Hospital and Faculty of Medicine, University of Valencia, Valencia, Spain
| | - Martin Herrmann
- Friedrich-Alexander-University Erlangen-Nürnberg (FAU), Department of Medicine 3, Rheumatology and Immunology, Universitätsklinikum Erlangen, Erlangen
| | - Christoph Hess
- Immunobiology Laboratory, Department of Biomedicine, University and University Hospital Basel, Basel, Switzerland
- Cambridge Institute of Therapeutic Immunology & Infectious Disease, Jeffrey Cheah Biomedical Centre, University of Cambridge, Cambridge, UK
| | - Thomas Höfer
- German Cancer Research Center (DKFZ), Division of Theoretical Systems Biology, Heidelberg, Germany
| | - Petra Hoffmann
- Regensburg Center for Interventional Immunology (RCI), Regensburg, Germany
- Department of Internal Medicine III, University Hospital Regensburg, Germany
| | - Kristin Hogquist
- Center for Immunology, University of Minnesota, Minneapolis, MN, USA
| | - Tristan Holland
- Institute of Experimental Immunology, University of Bonn, Germany
| | - Thomas Höllt
- Leiden Computational Biology Center, Leiden University Medical Center, Leiden, The Netherlands
- Computer Graphics and Visualization, Department of Intelligent Systems, TU Delft, Delft, The Netherlands
| | | | - Pleun Hombrink
- Department of Experimental Immunology, Amsterdam Infection and Immunity Institute, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands
- Department of Hematopoiesis, Sanquin Research and Landsteiner Laboratory, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands
| | - Jessica P. Houston
- Department of Chemical & Materials Engineering, New Mexico State University, Las Cruces, NM, USA
| | - Bimba F. Hoyer
- Rheumatologie/Klinische Immunologie, Klinik für Innere Medizin I und Exzellenzzentrum Entzündungsmedizin, Universitätsklinikum Schleswig-Holstein, Kiel, Germany
| | - Bo Huang
- Department of Immunology & National Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences (CAMS) & Peking Union Medical College, Beijing, China
| | - Fang-Ping Huang
- Institute for Advanced Study (IAS), Shenzhen University, Shenzhen, China
| | - Johanna E. Huber
- Institute for Immunology, Faculty of Medicine, Biomedical Center, LMU Munich, Planegg-Martinsried, Germany
| | - Jochen Huehn
- Experimental Immunology, Helmholtz Centre for Infection Research, Braunschweig, Germany
| | - Michael Hundemer
- Department of Hematology, Oncology and Rheumatology, University Heidelberg, Heidelberg, Germany
| | - Christopher A. Hunter
- Department of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - William Y. K. Hwang
- Department of Hematology, Singapore General Hospital, Singapore
- Cancer & Stem Cell Biology, Duke-NUS Medical School, Singapore
- Executive Offices, National Cancer Centre Singapore, Singapore
| | - Anna Iannone
- Department of Diagnostic Medicine, Clinical and Public Health, Univ. of Modena and Reggio Emilia, Modena, Italy
| | - Florian Ingelfinger
- Institute of Experimental Immunology, University of Zurich, Zurich, Switzerland
| | - Sabine M Ivison
- Department of Surgery, The University of British Columbia, Vancouver, Canada
- BC Children’s Hospital Research Institute, Vancouver, Canada
| | - Hans-Martin Jäck
- Division of Molecular Immunology, Nikolaus-Fiebiger-Center, Dept. of Internal Medicine III, University of Erlangen-Nuremberg, Erlangen, Germany
| | - Peter K. Jani
- Deutsches Rheuma-Forschungszentrum (DRFZ), an Institute of the Leibniz Association, Berlin, Germany
- Max Planck Institute for Infection Biology, Berlin, Germany
| | - Beatriz Jávega
- Laboratory of Cytomics, Joint Research Unit CIPF-UVEG, Department of Biochemistry and Molecular Biology, University of Valencia, Valencia, Spain
| | - Stipan Jonjic
- Department of Histology and Embryology/Center for Proteomics, Faculty of Medicine, University of Rijeka, Rijeka, Croatia
| | - Toralf Kaiser
- Deutsches Rheuma-Forschungszentrum (DRFZ), an Institute of the Leibniz Association, Berlin, Germany
| | - Tomas Kalina
- Department of Paediatric Haematology and Oncology, Second Faculty of Medicine, Charles University, Prague, Czech Republic
| | - Thomas Kamradt
- Jena University Hospital, Institute of Immunology, Jena, Germany
| | | | - Baerbel Keller
- Department of Rheumatology and Clinical Immunology, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
- Center for Chronic Immunodeficiency, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
| | - Steven L. C. Ketelaars
- Division of Molecular Oncology and Immunology, the Netherlands Cancer Institute, Amsterdam, The Netherlands
| | - Ahad Khalilnezhad
- Singapore Immunology Network (SIgN), A*STAR (Agency for Science, Technology and Research), Biopolis, Singapore
- Department of Microbiology and Immunology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
| | - Srijit Khan
- Department of Immunology, University of Toronto, Toronto, ON, Canada
| | - Jan Kisielow
- Institute of Molecular Health Sciences, ETH Zurich, Zürich, Switzerland
| | - Paul Klenerman
- Experimental Medicine Division, Nuffield Department of Medicine, University of Oxford, Oxford, UK
| | - Jasmin Knopf
- Friedrich-Alexander-University Erlangen-Nürnberg (FAU), Department of Medicine 3, Rheumatology and Immunology, Universitätsklinikum Erlangen, Erlangen
| | - Hui-Fern Koay
- Department of Microbiology and Immunology, Peter Doherty Institute for Infection and Immunity, University of Melbourne, Parkville, Victoria, Australia
| | - Katja Kobow
- Department of Neuropathology, Universitätsklinikum Erlangen, Germany
| | - Jay K. Kolls
- John W Deming Endowed Chair in Internal Medicine, Center for Translational Research in Infection and Inflammation Tulane School of Medicine, New Orleans, LA, USA
| | - Wan Ting Kong
- Singapore Immunology Network (SIgN), A*STAR (Agency for Science, Technology and Research), Biopolis, Singapore
| | - Manfred Kopf
- Institute of Molecular Health Sciences, ETH Zurich, Zürich, Switzerland
| | - Thomas Korn
- Department of Neurology, Technical University of Munich, Munich, Germany
| | - Katharina Kriegsmann
- Department of Hematology, Oncology and Rheumatology, University Heidelberg, Heidelberg, Germany
| | - Hendy Kristyanto
- Department of Rheumatology, Leiden University Medical Center, Leiden, The Netherlands
| | - Thomas Kroneis
- Division of Cell Biology, Histology & Embryology, Gottfried Schatz Research Center, Medical University of Graz, Graz, Austria
| | - Andreas Krueger
- Institute for Molecular Medicine, Goethe University Frankfurt, Frankfurt am Main, Germany
| | - Jenny Kühne
- Institute of Transplant Immunology, Hannover Medical School, MHH, Hannover, Germany
| | - Christian Kukat
- FACS & Imaging Core Facility, Max Planck Institute for Biology of Ageing, Cologne, Germany
| | - Désirée Kunkel
- Flow & Mass Cytometry Core Facility, Charité - Universitätsmedizin Berlin and Berlin Institute of Health, Berlin, Germany
- BCRT Flow Cytometry Lab, Berlin-Brandenburg Center for Regenerative Therapies, Charité - Universitätsmedizin Berlin
| | - Heike Kunze-Schumacher
- Institute for Molecular Medicine, Goethe University Frankfurt, Frankfurt am Main, Germany
| | - Tomohiro Kurosaki
- WPI Immunology Frontier Research Center, Osaka University, Osaka, Japan
| | - Christian Kurts
- Institute of Experimental Immunology, University of Bonn, Germany
| | - Pia Kvistborg
- Division of Molecular Oncology and Immunology, the Netherlands Cancer Institute, Amsterdam, The Netherlands
| | - Immanuel Kwok
- Singapore Immunology Network (SIgN), A*STAR (Agency for Science, Technology and Research), Biopolis, Singapore
- School of Biological Sciences, Nanyang Technological University, Singapore
| | - Jonathan Landry
- Genomics Core Facility, European Molecular Biology Laboratory (EMBL), Heidelberg, Germany
| | - Olivier Lantz
- INSERM U932, PSL University, Institut Curie, Paris, France
| | - Paola Lanuti
- Department of Medicine and Aging Sciences, Centre on Aging Sciences and Translational Medicine (Ce.S.I.-Me.T.), University “G. d’Annunzio” of Chieti-Pescara, Chieti, Italy
| | - Francesca LaRosa
- IRCCS Fondazione Don Carlo Gnocchi, Milan, Italy
- Milan Center for Neuroscience, University of Milano-Bicocca, Milan, Italy
| | - Agnès Lehuen
- Institut Cochin, CNRS8104, INSERM1016, Department of Endocrinology, Metabolism and Diabetes, Université de Paris, Paris, France
| | | | - Michael D. Leipold
- The Human Immune Monitoring Center (HIMC), Institute for Immunity, Transplantation and Infection, Stanford University School of Medicine, CA, USA
| | - Leslie Y.T. Leung
- Department of Immunology, University of Toronto, Toronto, ON, Canada
| | - Megan K. Levings
- Department of Surgery, The University of British Columbia, Vancouver, Canada
- BC Children’s Hospital Research Institute, Vancouver, Canada
- School of Biomedical Engineering, The University of British Columbia, Vancouver, Canada
| | - Andreia C. Lino
- Deutsches Rheuma-Forschungszentrum (DRFZ), an Institute of the Leibniz Association, Berlin, Germany
- Dept. Medicine/Rheumatology and Clinical Immunology, Charité Universitätsmedizin Berlin, Germany
| | - Francesco Liotta
- Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy
| | | | - Yanling Liu
- Department of Immunology, University of Toronto, Toronto, ON, Canada
| | - Hans-Gustaf Ljunggren
- Center for Infectious Medicine, Department of Medicine Huddinge, ANA Futura, Karolinska Institutet, Stockholm, Sweden
| | - Michael Lohoff
- Inst. f. Med. Mikrobiology and Hospital Hygiene, University of Marburg, Germany
| | - Giovanna Lombardi
- King’s College London, “Peter Gorer” Department of Immunobiology, London, UK
| | | | - Miguel López-Botet
- IMIM(Hospital de Mar Medical Research Institute), University Pompeu Fabra, Barcelona, Spain
| | - Amy E. Lovett-Racke
- Department of Microbial Infection and Immunity, Ohio State University, Columbus, OH, USA
| | - Erik Lubberts
- Department of Rheumatology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands
| | - Herve Luche
- Centre d’Immunophénomique - CIPHE (PHENOMIN), Aix Marseille Université (UMS3367), Inserm (US012), CNRS (UMS3367), Marseille, France
| | - Burkhard Ludewig
- Institute of Immunobiology, Kantonsspital St.Gallen, St. Gallen, Switzerland
| | - Enrico Lugli
- Laboratory of Translational Immunology, Humanitas Clinical and Research Center, Rozzano, Italy
- Flow Cytometry Core, Humanitas Clinical and Research Center, Milan, Italy
| | - Sebastian Lunemann
- Department of Virus Immunology, Heinrich Pette Institute, Leibniz Institute for Experimental Virology, Hamburg, Germany
| | - Holden T. Maecker
- Institute for Immunity, Transplantation, and Infection, Stanford University School of Medicine, Stanford, CA, USA
| | - Laura Maggi
- Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy
| | - Orla Maguire
- Flow and Image Cytometry Shared Resource, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA
| | - Florian Mair
- Fred Hutchinson Cancer Research Center, Vaccine and Infectious Disease Division, Seattle, WA, USA
| | - Kerstin H. Mair
- Institute of Immunology, Department of Pathobiology, University of Veterinary Medicine Vienna, Austria
- Christian Doppler Laboratory for Optimized Prediction of Vaccination Success in Pigs, Institute of Immunology, Department of Pathobiology, University of Veterinary Medicine Vienna, Austria
| | - Alberto Mantovani
- Istituto Clinico Humanitas IRCCS and Humanitas University, Pieve Emanuele, Milan, Italy
- William Harvey Research Institute, Queen Mary University, London, United Kingdom
| | - Rudolf A. Manz
- Institute for Systemic Inflammation Research, University of Luebeck, Luebeck, Germany
| | - Aaron J. Marshall
- Department of Immunology, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, MB, Canada
| | | | - Glòria Martrus
- Department of Virus Immunology, Heinrich Pette Institute, Leibniz Institute for Experimental Virology, Hamburg, Germany
| | - Ivana Marventano
- IRCCS Fondazione Don Carlo Gnocchi, Milan, Italy
- Milan Center for Neuroscience, University of Milano-Bicocca, Milan, Italy
| | - Wlodzimierz Maslinski
- National Institute of Geriatrics, Rheumatology and Rehabilitation, Department of Pathophysiology and Immunology, Warsaw, Poland
| | - Giuseppe Matarese
- Treg Cell Lab, Dipartimento di Medicina Molecolare e Biotecologie Mediche, Università di Napoli Federico II and Istituto per l’Endocrinologia e l’Oncologia Sperimentale, Consiglio Nazionale delle Ricerche (IEOS-CNR), Napoli, Italy
| | - Anna Vittoria Mattioli
- Department of Surgery, Medicine, Dentistry and Morphological Sciences, Univ. of Modena and Reggio Emilia, Modena, Italy
- Lab of Clinical and Experimental Immunology, Humanitas Clinical and Research Center, Rozzano, Milan, Italy
| | - Christian Maueröder
- Cell Clearance in Health and Disease Lab, VIB Center for Inflammation Research, Ghent, Belgium
- Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium
| | - Alessio Mazzoni
- Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy
| | - James McCluskey
- Department of Microbiology and Immunology, Peter Doherty Institute for Infection and Immunity, University of Melbourne, Parkville, Victoria, Australia
| | - Mairi McGrath
- Deutsches Rheuma-Forschungszentrum (DRFZ), an Institute of the Leibniz Association, Berlin, Germany
| | - Helen M. McGuire
- Ramaciotti Facility for Human Systems Biology, and Discipline of Pathology, The University of Sydney, Camperdown, Australia
| | - Iain B. McInnes
- Institute of Infection Immunity and Inflammation, College of Medical Veterinary and Life Sciences, University of Glasgow, Glasgow Biomedical Research Centre, Glasgow, UK
| | - Henrik E. Mei
- Deutsches Rheuma-Forschungszentrum (DRFZ), an Institute of the Leibniz Association, Berlin, Germany
| | - Fritz Melchers
- Deutsches Rheuma-Forschungszentrum (DRFZ), an Institute of the Leibniz Association, Berlin, Germany
- Max Planck Institute for Infection Biology, Berlin, Germany
| | - Susanne Melzer
- Clinical Trial Center Leipzig, University Leipzig, Leipzig, Germany
| | - Dirk Mielenz
- Division of Molecular Immunology, Nikolaus-Fiebiger-Center, Dept. of Internal Medicine III, University of Erlangen-Nuremberg, Erlangen, Germany
| | - Stephen D. Miller
- Interdepartmental Immunobiology Center, Dept. of Microbiology-Immunology, Northwestern Univ. Medical School, Chicago, IL, USA
| | - Kingston H.G. Mills
- Trinity College Dublin, School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Dublin, Ireland
| | - Hans Minderman
- Flow and Image Cytometry Shared Resource, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA
| | - Jenny Mjösberg
- Center for Infectious Medicine, Department of Medicine Huddinge, ANA Futura, Karolinska Institutet, Stockholm, Sweden
- Department of Clinical and Experimental Medine, Linköping University, Linköping, Sweden
| | - Jonni Moore
- Abramson Cancer Center Flow Cytometry and Cell Sorting Shared Resource, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA
| | - Barry Moran
- Trinity College Dublin, School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Dublin, Ireland
| | - Lorenzo Moretta
- Department of Immunology, IRCCS Bambino Gesu Children’s Hospital, Rome, Italy
| | - Tim R. Mosmann
- David H. Smith Center for Vaccine Biology and Immunology, University of Rochester Medical Center, Rochester, NY, USA
| | - Susann Müller
- Centre for Environmental Research - UFZ, Department Environmental Microbiology, Leipzig, Germany
| | - Gabriele Multhoff
- Institute for Innovative Radiotherapy (iRT), Experimental Immune Biology, Helmholtz Zentrum München, Neuherberg, Germany
- Radiation Immuno-Oncology Group, Center for Translational Cancer Research Technische Universität München (TranslaTUM), Klinikum rechts der Isar, Munich, Germany
| | - Luis Enrique Muñoz
- Friedrich-Alexander-University Erlangen-Nürnberg (FAU), Department of Medicine 3, Rheumatology and Immunology, Universitätsklinikum Erlangen, Erlangen
| | - Christian Münz
- Institute of Experimental Immunology, University of Zurich, Zurich, Switzerland
- Comprehensive Cancer Center Zurich, Switzerland
| | - Toshinori Nakayama
- Department of Immunology, Graduate School of Medicine, Chiba University, Chiba city, Chiba, Japan
| | - Milena Nasi
- Department of Surgery, Medicine, Dentistry and Morphological Sciences, Univ. of Modena and Reggio Emilia, Modena, Italy
| | - Katrin Neumann
- Institute of Experimental Immunology and Hepatology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Lai Guan Ng
- Singapore Immunology Network (SIgN), A*STAR (Agency for Science, Technology and Research), Biopolis, Singapore
- Department of Microbiology and Immunology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
- School of Biological Sciences, Nanyang Technological University, Singapore
- Discipline of Dermatology, University of Sydney, Sydney, New South Wales, Australia
- State Key Laboratory of Experimental Hematology, Institute of Hematology, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China
| | - Antonia Niedobitek
- Deutsches Rheuma-Forschungszentrum (DRFZ), an Institute of the Leibniz Association, Berlin, Germany
| | - Sussan Nourshargh
- Barts and The London School of Medicine and Dentistry, Queen Mary University of London, UK
| | - Gabriel Núñez
- Department of Pathology and Rogel Cancer Center, the University of Michigan, Ann Arbor, Michigan, USA
| | - José-Enrique O’Connor
- Laboratory of Cytomics, Joint Research Unit CIPF-UVEG, Department of Biochemistry and Molecular Biology, University of Valencia, Valencia, Spain
| | - Aaron Ochel
- Institute of Experimental Immunology and Hepatology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Anna Oja
- Department of Hematopoiesis, Sanquin Research and Landsteiner Laboratory, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands
| | - Diana Ordonez
- Flow Cytometry Core Facility, European Molecular Biology Laboratory (EMBL), Heidelberg, Germany
| | - Alberto Orfao
- Department of Medicine, Cancer Research Centre (IBMCC-CSIC/USAL), Cytometry Service, University of Salamanca, CIBERONC and Institute for Biomedical Research of Salamanca (IBSAL), Salamanca, Spain
| | - Eva Orlowski-Oliver
- Burnet Institute, AMREP Flow Cytometry Core Facility, Melbourne, Victoria, Australia
| | - Wenjun Ouyang
- Inflammation and Oncology, Research, Amgen Inc, South San Francisco, USA
| | | | - Raghavendra Palankar
- Department of Transfusion Medicine, Institute of Immunology and Transfusion Medicine, University Medicine Greifswald, Greifswald, Germany
| | - Isabel Panse
- Deutsches Rheuma-Forschungszentrum (DRFZ), an Institute of the Leibniz Association, Berlin, Germany
| | - Kovit Pattanapanyasat
- Center of Excellence for Flow Cytometry, Department of Research and Development, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand
| | - Malte Paulsen
- Flow Cytometry Core Facility, European Molecular Biology Laboratory (EMBL), Heidelberg, Germany
| | - Dinko Pavlinic
- Genomics Core Facility, European Molecular Biology Laboratory (EMBL), Heidelberg, Germany
| | - Livius Penter
- Department of Hematology, Oncology, and Tumor Immunology, Charité - Universitätsmedizin Berlin, Campus Virchow Klinikum, Berlin, Germany
| | - Pärt Peterson
- Institute of Biomedicine and Translational Medicine, University of Tartu, Tartu, Estonia
| | - Christian Peth
- Biophysics, R&D Engineering, Miltenyi Biotec GmbH, Bergisch Gladbach, Germany
| | - Jordi Petriz
- Functional Cytomics Group, Josep Carreras Leukaemia Research Institute, Campus ICO-Germans Trias i Pujol, Universitat Autònoma de Barcelona, UAB, Badalona, Spain
| | - Federica Piancone
- IRCCS Fondazione Don Carlo Gnocchi, Milan, Italy
- Milan Center for Neuroscience, University of Milano-Bicocca, Milan, Italy
| | - Winfried F. Pickl
- Institute of Immunology, Center for Pathophysiology, Infectiology and Immunology, Medical University of Vienna, Vienna, Austria
| | - Silvia Piconese
- Dipartimento di Medicina Interna e Specialità Mediche, Sapienza Università di Roma, Rome, Italy
- Istituto Pasteur - Fondazione Cenci Bolognetti, Rome, Italy
| | - Marcello Pinti
- Department of Life Sciences, University of Modena and Reggio Emilia, Modena, Italy
| | - A. Graham Pockley
- John van Geest Cancer Research Centre, Nottingham Trent University, Nottingham, UK
- Chromocyte Limited, Electric Works, Sheffield, UK
| | - Malgorzata Justyna Podolska
- Friedrich-Alexander-University Erlangen-Nürnberg (FAU), Department of Medicine 3, Rheumatology and Immunology, Universitätsklinikum Erlangen, Erlangen
- Department for Internal Medicine 3, Institute for Rheumatology and Immunology, AG Munoz, Universitätsklinikum Erlangen, Erlangen, Germany
| | - Zhiyong Poon
- Department of Hematology, Singapore General Hospital, Singapore
| | - Katharina Pracht
- Division of Molecular Immunology, Nikolaus-Fiebiger-Center, Dept. of Internal Medicine III, University of Erlangen-Nuremberg, Erlangen, Germany
| | - Immo Prinz
- Institute of Immunology, Hannover Medical School, Hannover, Germany
| | | | - Sally A. Quataert
- David H. Smith Center for Vaccine Biology and Immunology, University of Rochester Medical Center, Rochester, NY, USA
| | - Linda Quatrini
- Department of Immunology, IRCCS Bambino Gesu Children’s Hospital, Rome, Italy
| | - Kylie M. Quinn
- School of Biomedical and Health Sciences, RMIT University, Bundoora, Victoria, Australia
- Department of Biochemistry and Molecular Biology, Monash University, Clayton, Victoria, Australia
| | - Helena Radbruch
- Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Department of Neuropathology, Germany
| | - Tim R. D. J. Radstake
- Department of Rheumatology and Clinical Immunology, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands
| | - Susann Rahmig
- Regeneration in Hematopoiesis, Leibniz-Institute on Aging, Fritz-Lipmann-Institute (FLI), Jena, Germany
| | - Hans-Peter Rahn
- Preparative Flow Cytometry, Max-Delbrück-Centrum für Molekulare Medizin, Berlin, Germany
| | - Bartek Rajwa
- Bindley Biosciences Center, Purdue University, West Lafayette, IN, USA
| | - Gevitha Ravichandran
- Institute of Experimental Immunology and Hepatology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Yotam Raz
- Department of Internal Medicine, Groene Hart Hospital, Gouda, The Netherlands
| | - Jonathan A. Rebhahn
- David H. Smith Center for Vaccine Biology and Immunology, University of Rochester Medical Center, Rochester, NY, USA
| | | | - Dorothea Reimer
- Division of Molecular Immunology, Nikolaus-Fiebiger-Center, Dept. of Internal Medicine III, University of Erlangen-Nuremberg, Erlangen, Germany
| | | | - Ester B.M. Remmerswaal
- Department of Experimental Immunology, Amsterdam Infection and Immunity Institute, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands
- Renal Transplant Unit, Division of Internal Medicine, Academic Medical Centre, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands
| | - Lisa Richter
- Core Facility Flow Cytometry, Biomedical Center, Ludwig-Maximilians-University Munich, Germany
| | - Laura G. Rico
- Functional Cytomics Group, Josep Carreras Leukaemia Research Institute, Campus ICO-Germans Trias i Pujol, Universitat Autònoma de Barcelona, UAB, Badalona, Spain
| | - Andy Riddell
- Flow Cytometry Scientific Technology Platform, The Francis Crick Institute, London, UK
| | - Aja M. Rieger
- Department of Medical Microbiology and Immunology, University of Alberta, Alberta, Canada
| | - J. Paul Robinson
- Purdue University Cytometry Laboratories, Purdue University, West Lafayette, IN, USA
| | - Chiara Romagnani
- Deutsches Rheuma-Forschungszentrum (DRFZ), an Institute of the Leibniz Association, Berlin, Germany
- Charité - Universitätsmedizin Berlin, Medical Department I, Division of Gastroenterology, Infectiology and Rheumatology, Berlin, Germany
| | - Anna Rubartelli
- Cell Biology Unit, IRCCS Ospedale Policlinico San Martino, Genova, Italy
| | - Jürgen Ruland
- Institut für Klinische Chemie und Pathobiochemie, Fakultät für Medizin, Technische Universität München, München, Germany
| | - Armin Saalmüller
- Institute of Immunology, Department of Pathobiology, University of Veterinary Medicine Vienna, Austria
| | - Yvan Saeys
- Data Mining and Modeling for Biomedicine, VIB-UGent Center for Inflammation Research, Ghent, Belgium
- Department of Applied Mathematics, Computer Science and Statistics, Ghent University, Ghent, Belgium
| | - Takashi Saito
- RIKEN Center for Integrative Medical Sciences, Yokohama, Japan
| | - Shimon Sakaguchi
- WPI Immunology Frontier Research Center, Osaka University, Osaka, Japan
| | - Francisco Sala de-Oyanguren
- Flow Cytometry Facility, Ludwig Cancer Institute, Faculty of Medicine and Biology, University of Lausanne, Epalinges, Switzerland
| | - Yvonne Samstag
- Heidelberg University, Institute of Immunology, Section of Molecular Immunology, Heidelberg, Germany
| | - Sharon Sanderson
- Translational Immunology Laboratory, NIHR BRC, University of Oxford, Kennedy Institute of Rheumatology, Oxford, UK
| | - Inga Sandrock
- Institute of Immunology, Hannover Medical School, Hannover, Germany
| | - Angela Santoni
- Department of Molecular Medicine, Sapienza University of Rome, IRCCS, Neuromed, Pozzilli, Italy
| | - Ramon Bellmàs Sanz
- Institute of Transplant Immunology, Hannover Medical School, MHH, Hannover, Germany
| | - Marina Saresella
- IRCCS Fondazione Don Carlo Gnocchi, Milan, Italy
- Milan Center for Neuroscience, University of Milano-Bicocca, Milan, Italy
| | | | - Birgit Sawitzki
- Charité – Universitätsmedizin Berlin, and Berlin Institute of Health, Institute of Medical Immunology, Berlin, Germany
| | - Linda Schadt
- Institute of Experimental Immunology, University of Zurich, Zurich, Switzerland
- Comprehensive Cancer Center Zurich, Switzerland
| | - Alexander Scheffold
- Institut für Immunologie, Christian-Albrechts-Universität zu Kiel, Kiel, Germany
| | - Hans U. Scherer
- Department of Rheumatology, Leiden University Medical Center, Leiden, The Netherlands
| | - Matthias Schiemann
- Institut für Medizinische Mikrobiologie, Immunologie und Hygiene, Technische Universität München, Munich, Germany
| | - Frank A. Schildberg
- Clinic for Orthopedics and Trauma Surgery, University Hospital Bonn, Bonn, Germany
| | | | - Andreas Schlitzer
- Quantitative Systems Biology, Life & Medical Sciences Institute, University of Bonn, Bonn, Germany
| | - Josephine Schlosser
- Institute of Immunology, Centre for Infection Medicine, Department of Veterinary Medicine, Freie Universität Berlin, Germany
| | - Stephan Schmid
- Internal Medicine I, University Hospital Regensburg, Germany
| | - Steffen Schmitt
- Flow Cytometry Core Facility, German Cancer Research Centre (DKFZ), Heidelberg, Germany
| | - Kilian Schober
- Institut für Medizinische Mikrobiologie, Immunologie und Hygiene, Technische Universität München, Munich, Germany
| | - Daniel Schraivogel
- Genome Biology Unit, European Molecular Biology Laboratory (EMBL), Heidelberg, Germany
| | - Wolfgang Schuh
- Division of Molecular Immunology, Nikolaus-Fiebiger-Center, Dept. of Internal Medicine III, University of Erlangen-Nuremberg, Erlangen, Germany
| | - Thomas Schüler
- Institute of Molecular and Clinical Immunology, Otto-von-Guericke University, Magdeburg, Germany
| | - Reiner Schulte
- University of Cambridge, Cambridge Institute for Medical Research, Cambridge, UK
| | - Axel Ronald Schulz
- Deutsches Rheuma-Forschungszentrum (DRFZ), an Institute of the Leibniz Association, Berlin, Germany
| | - Sebastian R. Schulz
- Division of Molecular Immunology, Nikolaus-Fiebiger-Center, Dept. of Internal Medicine III, University of Erlangen-Nuremberg, Erlangen, Germany
| | - Cristiano Scottá
- King’s College London, “Peter Gorer” Department of Immunobiology, London, UK
| | - Daniel Scott-Algara
- Institut Pasteur, Cellular Lymphocytes Biology, Immunology Departement, Paris, France
| | - David P. Sester
- TRI Flow Cytometry Suite (TRI.fcs), Translational Research Institute, Wooloongabba, QLD, Australia
| | | | - Bruno Silva-Santos
- Instituto de Medicina Molecular João Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa, Portugal
| | | | - Katarzyna M. Sitnik
- Department of Vaccinology and Applied Microbiology, Helmholtz Centre for Infection Research, Braunschweig, Germany
| | - Silvano Sozzani
- Dept. Molecular Translational Medicine, University of Brescia, Brescia, Italy
| | - Daniel E. Speiser
- Department of Oncology, University of Lausanne and CHUV, Epalinges, Switzerland
| | | | - Anders Stahlberg
- Lundberg Laboratory for Cancer, Department of Pathology, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden
| | | | - Natalie Stanley
- Departments of Anesthesiology, Pain and Perioperative Medicine; Biomedical Data Sciences; and Pediatrics, Stanford University, Stanford, CA, USA
| | - Regina Stark
- Department of Experimental Immunology, Amsterdam Infection and Immunity Institute, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands
- Department of Hematopoiesis, Sanquin Research and Landsteiner Laboratory, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands
| | - Christina Stehle
- Deutsches Rheuma-Forschungszentrum (DRFZ), an Institute of the Leibniz Association, Berlin, Germany
- Charité - Universitätsmedizin Berlin, Medical Department I, Division of Gastroenterology, Infectiology and Rheumatology, Berlin, Germany
| | - Tobit Steinmetz
- Division of Molecular Immunology, Nikolaus-Fiebiger-Center, Dept. of Internal Medicine III, University of Erlangen-Nuremberg, Erlangen, Germany
| | - Hannes Stockinger
- Institute for Hygiene and Applied Immunology, Center for Pathophysiology, Infectiology and Immunology, Medical University of Vienna, Vienna, Austria
| | | | - Kiyoshi Takeda
- WPI Immunology Frontier Research Center, Osaka University, Osaka, Japan
| | - Leonard Tan
- Singapore Immunology Network (SIgN), A*STAR (Agency for Science, Technology and Research), Biopolis, Singapore
- Department of Microbiology and Immunology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
| | - Attila Tárnok
- Departement for Therapy Validation, Fraunhofer Institute for Cell Therapy and Immunology IZI, Leipzig, Germany
- Institute for Medical Informatics, Statistics and Epidemiology (IMISE), University of Leipzig, Leipzig, Germany
- Department of Precision Instruments, Tsinghua University, Beijing, China
| | - Gisa Tiegs
- Institute of Experimental Immunology and Hepatology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | | | - Julia Tornack
- Deutsches Rheuma-Forschungszentrum (DRFZ), an Institute of the Leibniz Association, Berlin, Germany
- BioGenes GmbH, Berlin, Germany
| | - Elisabetta Traggiai
- Novartis Biologics Center, Mechanistic Immunology Unit, Novartis Institute for Biomedical Research, NIBR, Basel, Switzerland
| | - Mohamed Trebak
- Department of Cellular and Molecular Physiology, Penn State University College of Medicine, PA, United States
| | - Timothy I.M. Tree
- Department of Immunobiology, School of Immunology and Microbial Sciences, King’s College London, UK
- National Institutes of Health Research Biomedical Research Centre at Guy’s and St. Thomas’ National Health Service, Foundation Trust and King’s College London, UK
| | | | - John Trowsdale
- Department of Pathology, University of Cambridge, Cambridge, UK
| | | | - Henning Ulrich
- Department of Biochemistry, Institute of Chemistry, University of São Paulo, São Paulo, SP, Brazil
| | - Sophia Urbanczyk
- Division of Molecular Immunology, Nikolaus-Fiebiger-Center, Dept. of Internal Medicine III, University of Erlangen-Nuremberg, Erlangen, Germany
| | - Willem van de Veen
- Swiss Institute of Allergy and Asthma Research (SIAF), University of Zurich, Davos, Switzerland
- Christine Kühne Center for Allergy Research and Education (CK-CARE), Davos, Switzerland
| | - Maries van den Broek
- Institute of Experimental Immunology, University of Zurich, Zurich, Switzerland
- Comprehensive Cancer Center Zurich, Switzerland
| | - Edwin van der Pol
- Vesicle Observation Center; Biomedical Engineering & Physics; Laboratory Experimental Clinical Chemistry; Amsterdam University Medical Centers, Location AMC, The Netherlands
| | - Sofie Van Gassen
- Data Mining and Modeling for Biomedicine, VIB-UGent Center for Inflammation Research, Ghent, Belgium
- Department of Applied Mathematics, Computer Science and Statistics, Ghent University, Ghent, Belgium
| | | | - René A.W. van Lier
- Department of Hematopoiesis, Sanquin Research and Landsteiner Laboratory, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands
| | - Marc Veldhoen
- Instituto de Medicina Molecular João Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa, Portugal
| | | | - Paulo Vieira
- Unit Lymphopoiesis, Department of Immunology, Institut Pasteur, Paris, France
| | - David Voehringer
- Department of Infection Biology, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nuremberg (FAU), Erlangen, Germany
| | - Hans-Dieter Volk
- BIH Center for Regenerative Therapies (BCRT) Charité Universitätsmedizin Berlin and Berlin Institute of Health, Core Unit ImmunoCheck
| | - Anouk von Borstel
- Infection and Immunity Program and Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Clayton, Victoria, Australia
- Australian Research Council Centre of Excellence in Advanced Molecular Imaging, Monash University, Clayton, Victoria, Australia
| | | | - Ari Waisman
- Institute for Molecular Medicine, University Medical Center of the Johannes Gutenberg University of Mainz, Mainz, Germany
| | | | - Paul K. Wallace
- Roswell Park Comprehensive Cancer Center, Elm and Carlton Streets, Buffalo, NY, USA
| | - Sa A. Wang
- Dept of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Xin M. Wang
- The Scientific Platforms, the Westmead Institute for Medical Research, the Westmead Research Hub, Westmead, New South Wales, Australia
| | | | | | - Klaus Warnatz
- Department of Rheumatology and Clinical Immunology, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
- Center for Chronic Immunodeficiency, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
| | - Gary Warnes
- Flow Cytometry Core Facility, Blizard Institute, Queen Mary London University, London, UK
| | - Sarah Warth
- BCRT Flow Cytometry Lab, Berlin-Brandenburg Center for Regenerative Therapies, Charité - Universitätsmedizin Berlin
| | - Claudia Waskow
- Regeneration in Hematopoiesis, Leibniz-Institute on Aging, Fritz-Lipmann-Institute (FLI), Jena, Germany
- Faculty of Biological Sciences, Friedrich Schiller University Jena, Jena, Germany
| | | | - Carsten Watzl
- Department for Immunology, Leibniz Research Centre for Working Environment and Human Factors at TU Dortmund (IfADo), Dortmund, Germany
| | - Leonie Wegener
- Biophysics, R&D Engineering, Miltenyi Biotec GmbH, Bergisch Gladbach, Germany
| | - Thomas Weisenburger
- Department of Biology, Nikolaus-Fiebiger-Center for Molecular Medicine, Friedrich-Alexander-University Erlangen-Nuremberg, Erlangen, Germany
| | - Annika Wiedemann
- Deutsches Rheuma-Forschungszentrum (DRFZ), an Institute of the Leibniz Association, Berlin, Germany
- Dept. Medicine/Rheumatology and Clinical Immunology, Charité Universitätsmedizin Berlin, Germany
| | - Jürgen Wienands
- Institute for Cellular & Molecular Immunology, University Medical Center Göttingen, Göttingen, Germany
| | - Anneke Wilharm
- Institute of Immunology, Hannover Medical School, Hannover, Germany
| | - Robert John Wilkinson
- Department of Infectious Disease, Imperial College London, UK
- Wellcome Centre for Infectious Diseases Research in Africa and Department of Medicine, Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Republic of South Africa
- Tuberculosis Laboratory, The Francis Crick Institute, London, UK
| | - Gerald Willimsky
- Cooperation Unit for Experimental and Translational Cancer Immunology, Institute of Immunology (Charité - Universitätsmedizin Berlin) and German Cancer Research Center (DKFZ), Berlin, Germany
| | - James B. Wing
- WPI Immunology Frontier Research Center, Osaka University, Osaka, Japan
| | - Rieke Winkelmann
- Institut für Immunologie, Christian-Albrechts-Universität zu Kiel, Kiel, Germany
| | - Thomas H. Winkler
- Department of Biology, Nikolaus-Fiebiger-Center for Molecular Medicine, Friedrich-Alexander-University Erlangen-Nuremberg, Erlangen, Germany
| | - Oliver F. Wirz
- Swiss Institute of Allergy and Asthma Research (SIAF), University of Zurich, Davos, Switzerland
| | - Alicia Wong
- Singapore Immunology Network (SIgN), A*STAR (Agency for Science, Technology and Research), Biopolis, Singapore
| | - Peter Wurst
- University Bonn, Medical Faculty, Bonn, Germany
| | - Jennie H. M. Yang
- Department of Immunobiology, School of Immunology and Microbial Sciences, King’s College London, UK
- National Institutes of Health Research Biomedical Research Centre at Guy’s and St. Thomas’ National Health Service, Foundation Trust and King’s College London, UK
| | - Juhao Yang
- Experimental Immunology, Helmholtz Centre for Infection Research, Braunschweig, Germany
| | - Maria Yazdanbakhsh
- Department of Parasitology, Leiden University Medical Center, Leiden, The Netherlands
| | | | - Alice Yue
- School of Computing Science, Simon Fraser University, Burnaby, Canada
| | - Hanlin Zhang
- Kennedy Institute of Rheumatology, University of Oxford, Oxford, UK
| | - Yi Zhao
- Department of Rheumatology and Immunology, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Susanne Maria Ziegler
- Department of Virus Immunology, Heinrich Pette Institute, Leibniz Institute for Experimental Virology, Hamburg, Germany
| | - Christina Zielinski
- German Center for Infection Research (DZIF), Munich, Germany
- Institute of Virology, Technical University of Munich, Munich, Germany
- TranslaTUM, Technical University of Munich, Munich, Germany
| | - Jakob Zimmermann
- Maurice Müller Laboratories (Department of Biomedical Research), Universitätsklinik für Viszerale Chirurgie und Medizin Inselspital, University of Bern, Bern, Switzerland
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Remedios KA, Zirak B, Sandoval PM, Lowe MM, Boda D, Henley E, Bhattrai S, Scharschmidt TC, Liao W, Naik HB, Rosenblum MD. The TNFRSF members CD27 and OX40 coordinately limit T H17 differentiation in regulatory T cells. Sci Immunol 2019; 3:3/30/eaau2042. [PMID: 30578350 DOI: 10.1126/sciimmunol.aau2042] [Citation(s) in RCA: 37] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2018] [Accepted: 11/01/2018] [Indexed: 12/13/2022]
Abstract
Regulatory T cells (Tregs) are closely related to TH17 cells and use aspects of the TH17-differentiation program for optimal immune regulation. In several chronic inflammatory human diseases, Tregs express IL-17A, suggesting that dysregulation of TH17-associated pathways in Tregs may result in either loss of suppressive function and/or conversion into pathogenic cells. The pathways that regulate the TH17 program in Tregs are poorly understood. We have identified two TNF receptor superfamily (TNFRSF) members, CD27 and OX40, that are preferentially expressed by skin-resident Tregs Both CD27 and OX40 signaling suppressed the expression of TH17-associated genes from Tregs in a cell-intrinsic manner in vitro and in vivo. However, only OX40 played a nonredundant role in promoting Treg accumulation. Tregs that lacked both CD27 and OX40 were defective in controlling skin inflammation and expressed high levels of IL-17A, as well as the master TH17 transcription factor, RORγt. Last, we found that CD27 expression was inversely correlated with Treg IL-17 production in skin of patients with psoriasis and hidradenitis suppurativa. Together, our results suggest that TNFRSF members play both redundant and distinct roles in regulating Treg plasticity in tissues.
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Affiliation(s)
- Kelly A Remedios
- Department of Dermatology, University of California, San Francisco, CA 94143, USA
| | - Bahar Zirak
- Department of Dermatology, University of California, San Francisco, CA 94143, USA
| | | | - Margaret M Lowe
- Department of Dermatology, University of California, San Francisco, CA 94143, USA
| | - Devi Boda
- Department of Dermatology, University of California, San Francisco, CA 94143, USA
| | - Evan Henley
- Department of Dermatology, University of California, San Francisco, CA 94143, USA
| | - Shrishti Bhattrai
- Department of Dermatology, University of California, San Francisco, CA 94143, USA
| | | | - Wilson Liao
- Department of Dermatology, University of California, San Francisco, CA 94143, USA
| | - Haley B Naik
- Department of Dermatology, University of California, San Francisco, CA 94143, USA
| | - Michael D Rosenblum
- Department of Dermatology, University of California, San Francisco, CA 94143, USA.
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Deng J, Zhao S, Zhang X, Jia K, Wang H, Zhou C, He Y. OX40 (CD134) and OX40 ligand, important immune checkpoints in cancer. Onco Targets Ther 2019; 12:7347-7353. [PMID: 31564917 PMCID: PMC6735535 DOI: 10.2147/ott.s214211] [Citation(s) in RCA: 57] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2019] [Accepted: 07/30/2019] [Indexed: 12/26/2022] Open
Abstract
Immunotherapy has shown promising results in cancer treatment. Research shows that most patients might be resistant to these therapies. So, new immune therapies are needed. OX40 (CD134) and OX40 ligand (OX40L), costimulatory molecules, express on different types of immune cells. The interaction between OX40 and OX40L (OX40/OX40L) induces the expansion and proliferation of T cells and decreases the immunosuppression of regulatory T (Treg) cells to enhance the immune response to the specific antigen. For the important role OX40 takes in the process of immunity, many clinical trials are focusing on OX40 to find out whether it may have active effects in clinical cancer treatment. The results of clinical trials are still not enough. So, we reviewed the OX40 and its ligand (OX40L) function in cancer, clinical trials with OX40/OX40L and the correlation between OX40/OX40L and other immune checkpoints to add more ideas to tumor feasible treatment.
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Affiliation(s)
- Juan Deng
- Department of Medical Oncology, Shanghai Pulmonary Hospital, Tongji University Medical School Cancer Institute, Tongji University School of Medicine, Shanghai 200433, People's Republic of China.,Medical School, Tongji University, Shanghai 200092, People's Republic of China
| | - Sha Zhao
- Department of Medical Oncology, Shanghai Pulmonary Hospital, Tongji University Medical School Cancer Institute, Tongji University School of Medicine, Shanghai 200433, People's Republic of China.,Medical School, Tongji University, Shanghai 200092, People's Republic of China
| | - Xiaoshen Zhang
- Department of Medical Oncology, Shanghai Pulmonary Hospital, Tongji University Medical School Cancer Institute, Tongji University School of Medicine, Shanghai 200433, People's Republic of China.,Medical School, Tongji University, Shanghai 200092, People's Republic of China
| | - Keyi Jia
- Department of Medical Oncology, Shanghai Pulmonary Hospital, Tongji University Medical School Cancer Institute, Tongji University School of Medicine, Shanghai 200433, People's Republic of China.,Medical School, Tongji University, Shanghai 200092, People's Republic of China
| | - Hao Wang
- Department of Medical Oncology, Shanghai Pulmonary Hospital, Tongji University Medical School Cancer Institute, Tongji University School of Medicine, Shanghai 200433, People's Republic of China.,Medical School, Tongji University, Shanghai 200092, People's Republic of China
| | - Caicun Zhou
- Department of Medical Oncology, Shanghai Pulmonary Hospital, Tongji University Medical School Cancer Institute, Tongji University School of Medicine, Shanghai 200433, People's Republic of China
| | - Yayi He
- Department of Medical Oncology, Shanghai Pulmonary Hospital, Tongji University Medical School Cancer Institute, Tongji University School of Medicine, Shanghai 200433, People's Republic of China
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Polesso F, Sarker M, Weinberg AD, Murray SE, Moran AE. OX40 Agonist Tumor Immunotherapy Does Not Impact Regulatory T Cell Suppressive Function. THE JOURNAL OF IMMUNOLOGY 2019; 203:2011-2019. [PMID: 31434709 DOI: 10.4049/jimmunol.1900696] [Citation(s) in RCA: 26] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/24/2019] [Accepted: 07/22/2019] [Indexed: 11/19/2022]
Abstract
OX40 is a costimulatory molecule from the TNFR family. In mice, it is expressed on Foxp3+ regulatory T cells (Tregs) constitutively and on conventional CD4 (Tconv) and CD8 T cells after Ag encounter. OX40 agonists are in clinical development to enhance antitumor immune responses, and one proposed mechanism of action is loss of Treg suppressive function. Studies have postulated that agonist OX40 therapy can impair Treg suppressive function. Using tools developed since the initial studies were published, we evaluated a direct effect of OX40 agonism on Treg function. We conclude that OX40 agonist Abs do not intrinsically impair Treg function but rather enhance Tconv cell IL-2 production, increasing Treg and Tconv cell proliferation. OX40-stimulated Tregs retain suppressive function, but also gain IFN-γ, TNF-α, and granzyme B expression. These data help resolve mechanistic questions regarding OX40 agonist immunotherapy and thus are relevant to developing combination therapies that target distinct T cell functions.
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Affiliation(s)
- Fanny Polesso
- Department of Cell, Developmental and Cancer Biology, Knight Cancer Institute, Oregon Health and Science University, Portland, OR 97239
| | - Minhaz Sarker
- Department of Molecular Microbiology and Immunology, Oregon Health and Science University, Portland, OR 97239
| | - Andrew D Weinberg
- Earle A. Chiles Research Institute, Robert W. Franz Cancer Research Center, Providence Portland Medical Center, Portland, OR 97213; and
| | - Susan E Murray
- Department of Molecular Microbiology and Immunology, Oregon Health and Science University, Portland, OR 97239.,Biology Department, University of Portland, Portland, OR 97203
| | - Amy E Moran
- Department of Cell, Developmental and Cancer Biology, Knight Cancer Institute, Oregon Health and Science University, Portland, OR 97239;
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Abstract
Despite continuous exposure to trillions of microbes, the intestinal immune system protects the mucosa by balancing barrier protection, tolerance, and immunity. As both sentinel and effector, the mucosal innate immune system plays a central role in coordinating these responses. By integrating signals from the intestinal microbiota, mononuclear phagocytes (MNPs) serve as a critical link in regulating effector functions of group 3 innate lymphoid cells (ILC3s). Our recent work identified the role for MNP production of the IBD-linked protein TNF-like ligand 1A (TL1A) in modulating microbial regulation of ILC3 barrier immunity. These findings highlight a broader role for ILC3s in local control of T cell immunity and their potential role in the pathogenesis and treatment of inflammatory disease.
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Affiliation(s)
- Jim G. Castellanos
- Jill Roberts Institute for Research in IBD, Division of Gastroenterology and Hepatology, Department of Medicine, Weill Cornell Medicine, New York, USA
| | - Randy S. Longman
- Jill Roberts Institute for Research in IBD, Division of Gastroenterology and Hepatology, Department of Medicine, Weill Cornell Medicine, New York, USA,CONTACT Randy S. Longman Jill Roberts Institute for Research in IBD, Division of Gastroenterology and Hepatology, Department of Medicine, Weill Cornell Medicine, New York, USA
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33
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Regulatory T cells in cancer immunosuppression - implications for anticancer therapy. Nat Rev Clin Oncol 2019; 16:356-371. [PMID: 30705439 DOI: 10.1038/s41571-019-0175-7] [Citation(s) in RCA: 1015] [Impact Index Per Article: 169.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
Regulatory T (Treg) cells, an immunosuppressive subset of CD4+ T cells characterized by the expression of the master transcription factor forkhead box protein P3 (FOXP3), are a component of the immune system with essential roles in maintaining self-tolerance. In addition, Treg cells can suppress anticancer immunity, thereby hindering protective immunosurveillance of neoplasia and hampering effective antitumour immune responses in tumour-bearing hosts, thus promoting tumour development and progression. Identification of the factors that are specifically expressed in Treg cells and/or that influence Treg cell homeostasis and function is important to understanding cancer pathogenesis and to identifying therapeutic targets. Immune-checkpoint inhibitors (ICIs) have provided a paradigm shift in the treatment of cancer. Most immune-checkpoint molecules are expressed in Treg cells, but the effects of ICIs on Treg cells, and thus the contributions of these cells to treatment responses, remain unclear. Notably, evidence indicates that ICIs targeting programmed cell death 1 (PD-1) might enhance the immunosuppressive function of Treg cells, whereas cytotoxic T lymphocyte antigen 4 (CTLA-4) inhibitors might deplete these cells. Thus, although manipulation of Treg cells is a promising anticancer therapeutic strategy, approaches to controlling these cells require further research. Herein, we discuss novel insights into the roles of Treg cells in cancer, which can hopefully be used to develop Treg cell-targeted therapies and facilitate immune precision medicine.
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Ryba-Stanisławowska M, Sakowska J, Zieliński M, Ławrynowicz U, Trzonkowski P. Regulatory T cells: the future of autoimmune disease treatment. Expert Rev Clin Immunol 2019; 15:777-789. [PMID: 31104510 DOI: 10.1080/1744666x.2019.1620602] [Citation(s) in RCA: 27] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Abstract
Introduction: CD4 + T regulatory cells (Tregs) have been described as the most potent immunosuppressive cells in the human body. They have been found to control autoimmunity, and clinical attempts have been made to apply them to treat autoimmune diseases. Some specific pathways utilized by Tregs in the regulation of immune response or Tregs directly as cellular products are tested in the clinic. Areas covered: Here, we present recent advances in the research on the biology and clinical applications of Tregs in the treatment of autoimmune diseases. Expert opinion: Regulatory T cells seem to be a promising tool for the treatment of autoimmune diseases. The development of both cell-based therapies and modern pharmacotherapies which affect Tregs may strongly improve the treatment of autoimmune disorders. Growing knowledge about Treg biology together with the latest biotechnology tools may give an opportunity for personalized therapies in these conditions.
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Affiliation(s)
- Monika Ryba-Stanisławowska
- a Department of Medical Immunology , Laboratory of Experimental Immunology, Medical University of Gdańsk , Debinki , Poland
| | - Justyna Sakowska
- b Department of Medical Immunology , Medical University of Gdańsk , Debinki , Poland
| | - Maciej Zieliński
- b Department of Medical Immunology , Medical University of Gdańsk , Debinki , Poland
| | - Urszula Ławrynowicz
- a Department of Medical Immunology , Laboratory of Experimental Immunology, Medical University of Gdańsk , Debinki , Poland
| | - Piotr Trzonkowski
- a Department of Medical Immunology , Laboratory of Experimental Immunology, Medical University of Gdańsk , Debinki , Poland
- b Department of Medical Immunology , Medical University of Gdańsk , Debinki , Poland
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Copsel S, Wolf D, Komanduri KV, Levy RB. The promise of CD4 +FoxP3 + regulatory T-cell manipulation in vivo: applications for allogeneic hematopoietic stem cell transplantation. Haematologica 2019; 104:1309-1321. [PMID: 31221786 PMCID: PMC6601084 DOI: 10.3324/haematol.2018.198838] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2019] [Accepted: 05/07/2019] [Indexed: 12/12/2022] Open
Abstract
CD4+FoxP3+ regulatory T cells (Tregs) are a non-redundant population critical for the maintenance of self-tolerance. Over the past decade, the use of these cells for therapeutic purposes in transplantation and autoimmune disease has emerged based on their capacity to inhibit immune activation. Basic science discoveries have led to identifying key receptors on Tregs that can regulate their proliferation and function. Notably, the understanding that IL-2 signaling is crucial for Treg homeostasis promoted the hypothesis that in vivo IL-2 treatment could provide a strategy to control the compartment. The use of low-dose IL-2 in vivo was shown to selectively expand Tregs versus other immune cells. Interestingly, a number of other Treg cell surface proteins, including CD28, CD45, IL-33R and TNFRSF members, have been identified which can also induce activation and proliferation of this population. Pre-clinical studies have exploited these observations to prevent and treat mice developing autoimmune diseases and graft-versus-host disease post-allogeneic hematopoietic stem cell transplantation. These findings support the development of translational strategies to expand Tregs in patients. Excitingly, the use of low-dose IL-2 for patients suffering from graft-versus-host disease and autoimmune disease has demonstrated increased Treg levels together with beneficial outcomes. To date, promising pre-clinical and clinical studies have directly targeted Tregs and clearly established the ability to increase their levels and augment their function in vivo. Here we review the evolving field of in vivo Treg manipulation and its application to allogeneic hematopoietic stem cell transplantation.
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Affiliation(s)
| | | | - Krishna V Komanduri
- Department of Microbiology and Immunology.,Sylvester Comprehensive Cancer Center.,Division of Transplantation and Cellular Therapy, Department of Medicine
| | - Robert B Levy
- Department of Microbiology and Immunology .,Division of Transplantation and Cellular Therapy, Department of Medicine.,Department of Ophthalmology, Miller School of Medicine, University of Miami, FL, USA
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36
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Alidadiani P, Eskandari N, Shaygannejad V, Dabiri A, Manian M, Jahanbani-Ardakani H, Mirmosayyeb O. Expression of OX40 Gene and its Serum Levels in Neuromyelitis Optica Patients. Biomol Concepts 2019; 10:62-67. [PMID: 30995203 DOI: 10.1515/bmc-2019-0007] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2018] [Accepted: 12/21/2018] [Indexed: 11/15/2022] Open
Abstract
Neuromyelitis optica (NMO), also known as Devic's disease, is an autoimmune disorder of the central nervous system (CNS) in which immune system cells and antibodies primarily attack the optic nerves and the spinal cord. OX40 (CD134) is a tumor necrosis factor (TNF)-receptor family member expressed primarily on activated CD4+ and CD8+ T-cells. In an autoimmune disease, OX40 is typically up-regulated at sites of inflammation, and increases in the number of peripheral CD4+ T-cells expressing OX40. OX40 and its ligand OX40L are key TNF members that augment T-cell expansion, cytokine production, and promote T-cell survival. The aim of this study was to evaluate and compare of OX40 gene expression and its serum levels in patients with NMO and healthy controls. Twenty sex-/age-matched healthy controls (HC) (median age = 32 years, 15 females/5 males) were engaged for the present study. Expression of OX40 at the transcript level and serum protein levels were measured by quantitative real-time polymerase chain reaction (qRT-PCR) and enzyme-linked immunosorbent assays, respectively. The results indicated OX40 expression in patients was significantly lower than in healthy controls (p = 0.001). However, the serum level of OX40 was not significantly different between groups (p = 0.37). In addition, the results indicated that CD134 expression was not age-related (p = 0.041). Overall, this study suggests to us that OX40 levels are not a suitable marker for diagnosis or treatment of NMO.
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Affiliation(s)
- Parya Alidadiani
- Department of Immunology, Faculty of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran; Department of Physiology, Applied Physiology Research Center, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Nahid Eskandari
- Department of Immunology, Faculty of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran; Department of Physiology, Applied Physiology Research Center, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Vahid Shaygannejad
- Isfahan Neuroscience Research Center, Department of Neurology, Alzahra Hospital, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Arezou Dabiri
- Department of Immunology, International Campus, Shahid Sadoughi University of Medical Sciences, Yazd, Iran
| | - Mostafa Manian
- Department of Immunology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | | | - Omid Mirmosayyeb
- Isfahan Neuroscience Research Center, Department of Neurology, Alzahra Hospital, Isfahan University of Medical Sciences, Isfahan, Iran
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Increased Expressions of OX40 and OX40 Ligand in Patients with Primary Immune Thrombocytopenia. J Immunol Res 2019; 2019:6804806. [PMID: 30944836 PMCID: PMC6421740 DOI: 10.1155/2019/6804806] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2018] [Revised: 01/19/2019] [Accepted: 02/12/2019] [Indexed: 12/19/2022] Open
Abstract
Background OX40, which is also known as tumor necrosis factor receptor superfamily member 4 (TNFRSF4), and its ligand (OX40L) play a critical role in the pathogenesis of autoimmune diseases. Immune thrombocytopenia (ITP), a hemorrhagic autoimmune disorder, is characterized by low platelet counts that are predominantly caused by antiplatelet autoantibodies. In this study, we firstly investigated the clinical significance of OX40 and OX40L expression in the pathogenesis of ITP in patients. Methods Fifty-four newly diagnosed ITP patients and 24 healthy controls (HCs) were enrolled in this study. The percentage of OX40+CD4+T cells among CD4+T cells was analyzed by flow cytometry, and the expression levels of OX40 and OX40L mRNA were analyzed by quantitative real-time PCR. Plasma soluble OX40L (sOX40L) levels were analyzed by ELISA, and plasma levels of antiplatelet autoantibodies were analyzed by a solid-phase technique. Results Compared with HCs, the frequencies of OX40+CD4+T cells were significantly increased in ITP patients, particularly in patients with positive antiplatelet autoantibodies compared to those with negative antiplatelet autoantibodies. The elevated frequencies of OX40+CD4+T cells were negatively correlated with low platelet counts in patients with positive antiplatelet autoantibodies. Plasma sOX40L levels in ITP patients were significantly greater than those in HCs and increased in patients with positive antiplatelet autoantibodies compared to those with negative antiplatelet autoantibodies. Plasma sOX40L levels were negatively correlated with low platelet counts in patients with positive antiplatelet autoantibodies. Additionally, the mRNA expression levels of OX40 and OX40L in PBMCs from ITP patients were also notably greater than those from HCs, and the expression levels of OX40 and OX40L were significantly different in ITP patients with positive and negative antiplatelet autoantibodies. Conclusion These data indicated that increased expression levels of OX40 and OX40L were involved in the pathogenesis of ITP, and OX40 and OX40L may be valuable therapeutic targets for ITP.
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Hagihara Y, Yoshimatsu Y, Mikami Y, Takada Y, Mizuno S, Kanai T. Epigenetic regulation of T helper cells and intestinal pathogenicity. Semin Immunopathol 2019; 41:379-399. [PMID: 30891628 DOI: 10.1007/s00281-019-00732-9] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2019] [Accepted: 03/05/2019] [Indexed: 02/06/2023]
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39
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Regulatory T cell adaptation in the intestine and skin. Nat Immunol 2019; 20:386-396. [PMID: 30890797 DOI: 10.1038/s41590-019-0351-z] [Citation(s) in RCA: 118] [Impact Index Per Article: 19.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2018] [Accepted: 02/14/2019] [Indexed: 02/06/2023]
Abstract
The intestine and skin are distinct microenvironments with unique physiological functions and are continually exposed to diverse environmental challenges. Host adaptation at these sites is an active process that involves interaction between immune cells and tissue cells. Regulatory T cells (Treg cells) play a pivotal role in enforcing homeostasis at barrier surfaces, illustrated by the development of intestinal and skin inflammation in diseases caused by primary deficiency in Treg cells. Treg cells at barrier sites are phenotypically distinct from their lymphoid-organ counterparts, and these 'tissue' signatures often reflect their tissue-adapted function. We discuss current understanding of Treg cell adaptation in the intestine and skin, including unique phenotypes, functions and metabolic demands, and how increased knowledge of Treg cells at barrier sites might guide precision medicine therapies.
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40
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Wang KQ, Wen HZ, Wu QY, Zheng QW, Wang MW, Wan ZW, Yang D, Hao WW. Factors involved in balance of Th17/Treg cells: Clinical implications in inflammatory bowel disease. Shijie Huaren Xiaohua Zazhi 2019; 27:336-340. [DOI: 10.11569/wcjd.v27.i5.336] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
T-helper 17 (Th17) cells promote tissue inflammation and T-regulatory (Treg) cells inhibit autoimmunity in inflammatory bowel disease (IBD). Thus, the balance between Th17 and Treg cells is crucial. Many factors that influence the generation and maintenance of these cells are also important for appropriate regulation of the Th17/Treg balance; these include TCR signals, costimulatory signals, cytokine signals, Foxp3 stability, metabolic processes, and the microbiota. This article will focus on what we know about these factors, their roles in regulating the Th17/Treg balance, and their clinical implications in IBD.
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Affiliation(s)
- Kai-Qiang Wang
- Department of Gastroenterology, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 200437, China
| | - Hong-Zhu Wen
- Research Institute of Spleen and Stomach Diseases, Shanghai Institute of Traditional Chinese Medicine, Shanghai 200032, China
| | - Qing-Yuan Wu
- Research Institute of Spleen and Stomach Diseases, Shanghai Institute of Traditional Chinese Medicine, Shanghai 200032, China
| | - Qin-Wei Zheng
- Department of Gastroenterology, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 200437, China
| | - Meng-Wan Wang
- Department of Gastroenterology, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 200437, China
| | - Zhi-Wei Wan
- Department of Gastroenterology, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 200437, China
| | - Dan Yang
- Department of Gastroenterology, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 200437, China
| | - Wei-Wei Hao
- Department of Gastroenterology, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 200437, China,Research Institute of Spleen and Stomach Diseases, Shanghai Institute of Traditional Chinese Medicine, Shanghai 200032, China
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ILC3-derived OX40L is essential for homeostasis of intestinal Tregs in immunodeficient mice. Cell Mol Immunol 2019; 17:163-177. [PMID: 30760919 DOI: 10.1038/s41423-019-0200-x] [Citation(s) in RCA: 31] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2018] [Accepted: 12/27/2018] [Indexed: 12/13/2022] Open
Abstract
OX40L is one of the co-stimulatory molecules that can be expressed by splenic lymphoid tissue inducer (Lti) cells, a subset of group 3 innate lymphoid cells (ILC3s). OX40L expression in subsets of intestinal ILC3s and the molecular regulation of OX40L expression in ILC3s are unknown. Here, we showed intestinal ILC3s marked as an OX40Lhigh population among all the intestinal leukocytes and were the dominant source of OX40L in Rag1-/- mice. All ILC3 subsets expressed OX40L, and NCR-ILC3s were the most abundant source of OX40L. The expression of OX40L in ILC3s could be upregulated during inflammation. In addition to tumor necrosis factor (TNF)-like cytokine 1A (TL1A), which has been known as a trigger for OX40L, we found that Poly (I:C) representing viral stimulus promoted OX40L expression in ILC3s via a cell-autonomous manner. Furthermore, we demonstrated that IL-7-STAT5 signaling sustained OX40L expression by ILC3s. Intestinal regulatory T cells (Tregs), most of which expressed OX40, had defective expansion in chimeric mice, in which ILC3s were specifically deficient for OX40L expression. Consistently, co-localization of Tregs and ILC3s was found in the cryptopatches of the intestine, which suggests the close interaction between ILC3s and Tregs. Our study has unveiled the crosstalk between Tregs and ILC3s in mucosal tissues through OX40-OX40L signaling, which is crucial for the homeostasis of intestinal Tregs.
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Wing JB, Tay C, Sakaguchi S. Control of Regulatory T Cells by Co-signal Molecules. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2019; 1189:179-210. [DOI: 10.1007/978-981-32-9717-3_7] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
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43
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Castellanos JG, Woo V, Viladomiu M, Putzel G, Lima S, Diehl GE, Marderstein AR, Gandara J, Perez AR, Withers DR, Targan SR, Shih DQ, Scherl EJ, Longman RS. Microbiota-Induced TNF-like Ligand 1A Drives Group 3 Innate Lymphoid Cell-Mediated Barrier Protection and Intestinal T Cell Activation during Colitis. Immunity 2018; 49:1077-1089.e5. [PMID: 30552020 PMCID: PMC6301104 DOI: 10.1016/j.immuni.2018.10.014] [Citation(s) in RCA: 124] [Impact Index Per Article: 17.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2018] [Revised: 08/08/2018] [Accepted: 10/17/2018] [Indexed: 12/27/2022]
Abstract
Inflammatory bowel disease (IBD) results from a dysregulated interaction between the microbiota and a genetically susceptible host. Genetic studies have linked TNFSF15 polymorphisms and its protein TNF-like ligand 1A (TL1A) with IBD, but the functional role of TL1A is not known. Here, we found that adherent IBD-associated microbiota induced TL1A release from CX3CR1+ mononuclear phagocytes (MNPs). Using cell-specific genetic deletion models, we identified an essential role for CX3CR1+MNP-derived TL1A in driving group 3 innate lymphoid cell (ILC3) production of interleukin-22 and mucosal healing during acute colitis. In contrast to this protective role in acute colitis, TL1A-dependent expression of co-stimulatory molecule OX40L in MHCII+ ILC3s during colitis led to co-stimulation of antigen-specific T cells that was required for chronic T cell colitis. These results identify a role for ILC3s in activating intestinal T cells and reveal a central role for TL1A in promoting ILC3 barrier immunity during colitis.
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Affiliation(s)
- Jim G Castellanos
- Jill Roberts Institute for Research in IBD, Weill Cornell Medicine, New York, NY, 10021, USA
| | - Viola Woo
- Jill Roberts Institute for Research in IBD, Weill Cornell Medicine, New York, NY, 10021, USA
| | - Monica Viladomiu
- Jill Roberts Institute for Research in IBD, Weill Cornell Medicine, New York, NY, 10021, USA
| | - Gregory Putzel
- Jill Roberts Institute for Research in IBD, Weill Cornell Medicine, New York, NY, 10021, USA
| | - Svetlana Lima
- Jill Roberts Institute for Research in IBD, Weill Cornell Medicine, New York, NY, 10021, USA
| | - Gretchen E Diehl
- Alkek Center for Metagenomics and Microbiome Research, Baylor College of Medicine, Houston, TX, 77030, USA
| | - Andrew R Marderstein
- Jill Roberts Institute for Research in IBD, Weill Cornell Medicine, New York, NY, 10021, USA
| | - Jorge Gandara
- Jill Roberts Institute for Research in IBD, Weill Cornell Medicine, New York, NY, 10021, USA
| | - Alexendar R Perez
- Jill Roberts Institute for Research in IBD, Weill Cornell Medicine, New York, NY, 10021, USA
| | - David R Withers
- Institute of Immunology and Immunotherapy, College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK
| | - Stephan R Targan
- F. Widjaja Foundation, Inflammatory Bowel and Immunology Research Institute, Cedars-Sinai Medical Center, Los Angeles, California, 90048, USA
| | - David Q Shih
- F. Widjaja Foundation, Inflammatory Bowel and Immunology Research Institute, Cedars-Sinai Medical Center, Los Angeles, California, 90048, USA
| | - Ellen J Scherl
- Jill Roberts Center for IBD, Weill Cornell Medicine, New York, NY, 10021, USA
| | - Randy S Longman
- Jill Roberts Institute for Research in IBD, Weill Cornell Medicine, New York, NY, 10021, USA; Jill Roberts Center for IBD, Weill Cornell Medicine, New York, NY, 10021, USA.
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Kumar P, Bhattacharya P, Prabhakar BS. A comprehensive review on the role of co-signaling receptors and Treg homeostasis in autoimmunity and tumor immunity. J Autoimmun 2018; 95:77-99. [PMID: 30174217 PMCID: PMC6289740 DOI: 10.1016/j.jaut.2018.08.007] [Citation(s) in RCA: 145] [Impact Index Per Article: 20.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2018] [Revised: 08/22/2018] [Accepted: 08/26/2018] [Indexed: 12/22/2022]
Abstract
The immune system ensures optimum T-effector (Teff) immune responses against invading microbes and tumor antigens while preventing inappropriate autoimmune responses against self-antigens with the help of T-regulatory (Treg) cells. Thus, Treg and Teff cells help maintain immune homeostasis through mutual regulation. While Tregs can contribute to tumor immune evasion by suppressing anti-tumor Teff response, loss of Treg function can result in Teff responses against self-antigens leading to autoimmune disease. Thus, loss of homeostatic balance between Teff/Treg cells is often associated with both cancer and autoimmunity. Co-stimulatory and co-inhibitory receptors, collectively known as co-signaling receptors, play an indispensable role in the regulation of Teff and Treg cell expansion and function and thus play critical roles in modulating autoimmune and anti-tumor immune responses. Over the past three decades, considerable efforts have been made to understand the biology of co-signaling receptors and their role in immune homeostasis. Mutations in co-inhibitory receptors such as CTLA4 and PD1 are associated with Treg dysfunction, and autoimmune diseases in mice and humans. On the other hand, growing tumors evade immune surveillance by exploiting co-inhibitory signaling through expression of CTLA4, PD1 and PDL-1. Immune checkpoint blockade (ICB) using anti-CTLA4 and anti-PD1 has drawn considerable attention towards co-signaling receptors in tumor immunology and created renewed interest in studying other co-signaling receptors, which until recently have not been as well studied. In addition to co-inhibitory receptors, co-stimulatory receptors like OX40, GITR and 4-1BB have also been widely implicated in immune homeostasis and T-cell stimulation, and use of agonistic antibodies against OX40, GITR and 4-1BB has been effective in causing tumor regression. Although ICB has seen unprecedented success in cancer treatment, autoimmune adverse events arising from ICB due to loss of Treg homeostasis poses a major obstacle. Herein, we comprehensively review the role of various co-stimulatory and co-inhibitory receptors in Treg biology and immune homeostasis, autoimmunity, and anti-tumor immunity. Furthermore, we discuss the autoimmune adverse events arising upon targeting these co-signaling receptors to augment anti-tumor immune responses.
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Affiliation(s)
- Prabhakaran Kumar
- Department of Microbiology and Immunology, University of Illinois-College of Medicine, Chicago, IL, USA
| | - Palash Bhattacharya
- Department of Microbiology and Immunology, University of Illinois-College of Medicine, Chicago, IL, USA
| | - Bellur S Prabhakar
- Department of Microbiology and Immunology, University of Illinois-College of Medicine, Chicago, IL, USA; Department of Ophthalmology, Associate Dean for Technological Innovation and Training, University of Illinois College of Medicine, Room E-705, (M/C 790), 835 S. Wolcott Ave, Chicago, IL, 60612, USA.
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45
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CXCR6 +ST2 + memory T helper 2 cells induced the expression of major basic protein in eosinophils to reduce the fecundity of helminth. Proc Natl Acad Sci U S A 2018; 115:E9849-E9858. [PMID: 30275296 DOI: 10.1073/pnas.1714731115] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/16/2023] Open
Abstract
Memory T helper (mTh) cells play important roles in the reinfection of pathogens and drive the pathogenesis of diseases. While recent studies have characterized the pathogenic mTh2 cell subpopulations driving allergic inflammation, those that induce immune responses against helminth infection remain unknown. We found that IL-5-producing CXCR6+ST2+CD44+ mTh2 cells play a crucial role in the IL-33-dependent inhibition of the fecundity of helminth, whereas other ST2- mTh2 cells do not. Although both cell types induced the infiltration of granulocytes, especially eosinophils, into the lungs in response to helminth infection, the ST2+ mTh2 cell-induced eosinophils expressed higher levels of major basic protein (MBP), which is important for reducing the fecundity of Nippostrongylus brasiliensis (Nb), than ST2- mTh2 cell-induced ones. Notably, we also found that ST2+ Treg cells but not ST2- Treg cells suppressed CXCR6+ST2+ mTh2 cell-mediated immune responses. Taken together, these findings show that we identified a mechanism against helminth elicited by a subpopulation of IL-5-producing mTh2 cells through the accumulation of eosinophils strongly expressing MBP in the lungs.
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Resolution of chronic inflammatory disease: universal and tissue-specific concepts. Nat Commun 2018; 9:3261. [PMID: 30111884 PMCID: PMC6093916 DOI: 10.1038/s41467-018-05800-6] [Citation(s) in RCA: 270] [Impact Index Per Article: 38.6] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2018] [Accepted: 06/22/2018] [Indexed: 12/21/2022] Open
Abstract
Inflammation and its resolution is under-studied in medicine despite being essential for understanding the development of chronic inflammatory disease. In this review article, we discuss the resolution of inflammation in both a biological and translational context. We introduce the concept of impaired resolution leading to diseases like rheumatoid arthritis, Crohn's disease, and asthma, as well as the cellular and molecular components that contribute to resolution of joint, gut, and lung inflammation, respectively. Finally, we discuss potential intervention strategies for fostering the resolution process, and their implications for the therapy of inflammatory diseases.
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Shitara K, Nishikawa H. Regulatory T cells: a potential target in cancer immunotherapy. Ann N Y Acad Sci 2018; 1417:104-115. [DOI: 10.1111/nyas.13625] [Citation(s) in RCA: 141] [Impact Index Per Article: 20.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2017] [Accepted: 01/11/2018] [Indexed: 12/11/2022]
Affiliation(s)
- Kohei Shitara
- Department of Gastroenterology and Gastrointestinal Oncology; National Cancer Center Hospital East; Chiba Japan
| | - Hiroyoshi Nishikawa
- Division of Cancer Immunology, Research Institute/EPOC; National Cancer Center; Tokyo/Chiba Japan
- Department of Immunology; Nagoya University Graduate School of Medicine; Nagoya Japan
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Buchan SL, Rogel A, Al-Shamkhani A. The immunobiology of CD27 and OX40 and their potential as targets for cancer immunotherapy. Blood 2018; 131:39-48. [PMID: 29118006 DOI: 10.1182/blood-2017-07-741025] [Citation(s) in RCA: 185] [Impact Index Per Article: 26.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2017] [Accepted: 10/08/2017] [Indexed: 12/13/2022] Open
Abstract
In recent years, monoclonal antibodies (mAbs) able to reinvigorate antitumor T-cell immunity have heralded a paradigm shift in cancer treatment. The most high profile of these mAbs block the inhibitory checkpoint receptors PD-1 and CTLA-4 and have improved life expectancy for patients across a range of tumor types. However, it is becoming increasingly clear that failure of some patients to respond to checkpoint inhibition is attributable to inadequate T-cell priming. For full T-cell activation, 2 signals must be received, and ligands providing the second of these signals, termed costimulation, are often lacking in tumors. Members of the TNF receptor superfamily (TNFRSF) are key costimulators of T cells during infection, and there has been an increasing interest in harnessing these receptors to augment tumor immunity. We here review the immunobiology of 2 particularly promising TNFRSF target receptors, CD27 and OX40, and their respective ligands, CD70 and OX40L, focusing on their role within a tumor setting. We describe the influence of CD27 and OX40 on human T cells based on in vitro studies and on the phenotypes of several recently described individuals exhibiting natural deficiencies in CD27/CD70 and OX40. Finally, we review key literature describing progress in elucidating the efficacy and mode of action of OX40- and CD27-targeting mAbs in preclinical models and provide an overview of current clinical trials targeting these promising receptor/ligand pairings in cancer.
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Affiliation(s)
- Sarah L Buchan
- Cancer Sciences Unit, Faculty of Medicine, University of Southampton, Southampton, United Kingdom
| | - Anne Rogel
- Cancer Sciences Unit, Faculty of Medicine, University of Southampton, Southampton, United Kingdom
| | - Aymen Al-Shamkhani
- Cancer Sciences Unit, Faculty of Medicine, University of Southampton, Southampton, United Kingdom
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Shah SV, Manickam C, Ram DR, Reeves RK. Innate Lymphoid Cells in HIV/SIV Infections. Front Immunol 2017; 8:1818. [PMID: 29326704 PMCID: PMC5733347 DOI: 10.3389/fimmu.2017.01818] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2017] [Accepted: 12/04/2017] [Indexed: 12/12/2022] Open
Abstract
Over the past several years, new populations of innate lymphocytes have been described in mice and primates that are critical for mucosal homeostasis, microbial regulation, and immune defense. Generally conserved from mice to humans, innate lymphoid cells (ILC) have been divided primarily into three subpopulations based on phenotypic and functional repertoires: ILC1 bear similarities to natural killer cells; ILC2 have overlapping functions with TH2 cells; and ILC3 that share many functions with TH17/TH22 cells. ILC are specifically enriched at mucosal surfaces and are possibly one of the earliest responders during viral infections besides being involved in the homeostasis of gut-associated lymphoid tissue and maintenance of gut epithelial barrier integrity. Burgeoning evidence also suggests that there is an early and sustained abrogation of ILC function and numbers during HIV and pathogenic SIV infections, most notably ILC3 in the gastrointestinal tract, which leads to disruption of the mucosal barrier and dysregulation of the local immune system. A better understanding of the direct or indirect mechanisms of loss and dysfunction will be critical to immunotherapeutics aimed at restoring these cells. Herein, we review the current literature on ILC with a particular emphasis on ILC3 and their role(s) in mucosal immunology and the significance of disrupting the ILC niche during HIV and SIV infections.
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Affiliation(s)
- Spandan V Shah
- Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, United States
| | - Cordelia Manickam
- Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, United States
| | - Daniel R Ram
- Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, United States
| | - R Keith Reeves
- Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, United States
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50
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Chien CH, Chiang BL. Regulatory T cells induced by B cells: a novel subpopulation of regulatory T cells. J Biomed Sci 2017; 24:86. [PMID: 29151021 PMCID: PMC5694621 DOI: 10.1186/s12929-017-0391-3] [Citation(s) in RCA: 65] [Impact Index Per Article: 8.1] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2017] [Accepted: 11/03/2017] [Indexed: 11/10/2022] Open
Abstract
Regulatory T cells play a crucial role in the homeostasis of the immune response. In addition to CD4+Foxp3+ regulatory T cells, several subsets of Foxp3- regulatory T cells, such as T helper 3 (Th3) cells and type 1 regulatory T (Tr1) cells, have been described in mice and human. Accumulating evidence shows that naïve B cells contribute to tolerance and are able to promote regulatory T cell differentiation. Naïve B cells can convert CD4+CD25- T cells into CD25+Foxp3- regulatory T cells, named Treg-of-B cells by our group. Treg-of-B cells express LAG3, ICOS, GITR, OX40, PD1, and CTLA4 and secrete IL-10. Intriguingly, B-T cell-cell contact but not IL-10 is essential for Treg-of-B cells induction. Moreover, Treg-of-B cells possess both IL-10-dependent and IL-10-independent inhibitory functions. Treg-of-B cells exert suppressive activities in antigen-specific and non-antigen-specific manners in vitro and in vivo. Here, we review the phenotype and function of Foxp3+ regulatory T cells, Th3 cells, Tr1 cells, and Treg-of-B cells.
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Affiliation(s)
- Chien-Hui Chien
- Graduate Institute of Clinical Medicine, National Taiwan University, Taipei City, 10048, Taiwan, Republic of China
| | - Bor-Luen Chiang
- Graduate Institute of Clinical Medicine, National Taiwan University, Taipei City, 10048, Taiwan, Republic of China. .,Department of Medical Research, National Taiwan University Hospital, Taipei City, 10002, Taiwan, Republic of China.
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