|
1
|
Lyu Z, Niu S, Fang Y, Chen Y, Li YR, Yang L. Addressing graft-versus-host disease in allogeneic cell-based immunotherapy for cancer. Exp Hematol Oncol 2025; 14:66. [PMID: 40317083 PMCID: PMC12046680 DOI: 10.1186/s40164-025-00654-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2025] [Accepted: 04/13/2025] [Indexed: 05/04/2025] Open
Abstract
Allogeneic cell-based immunotherapies, particularly CAR-T cell therapy, represent a significant advancement in cancer treatment, offering scalable and consistent alternatives to autologous therapies. However, their widespread use is limited by the risk of graft-versus-host disease (GvHD). This review provides a comprehensive overview of GvHD in the context of allogeneic cell-based cancer immunotherapy and evaluates current strategies to mitigate its effects. Key strategies include genetic engineering approaches such as T cell receptor (TCR) knockout (KO) and T cell receptor alpha constant (TRAC) CAR knock-in. Alternative immune cell types like natural killer (NK) cells and natural killer T (NKT) cells offer potential solutions due to their lower alloreactivity. Additionally, stem cell technology, utilizing induced pluripotent stem cells (iPSCs), enables standardized and scalable production of engineered CAR-T cells. Clinical trials evaluating these strategies, such as UCART19 and CTX110, demonstrate promising results in preventing GvHD while maintaining anti-tumor efficacy. The review also addresses manufacturing considerations for allogeneic cell products and the challenges in translating preclinical findings into clinical success. By addressing these challenges, allogeneic cell-based immunotherapy continues to advance, paving the way for more accessible, scalable, and effective cancer treatments.
Collapse
Affiliation(s)
- Zibai Lyu
- Department of Microbiology, Immunology & Molecular Genetics, University of California, Los Angeles, CA, 90095, USA
- Department of Bioengineering, University of California, Los Angeles, CA, 90095, USA
| | - Siyue Niu
- Department of Microbiology, Immunology & Molecular Genetics, University of California, Los Angeles, CA, 90095, USA
- Department of Bioengineering, University of California, Los Angeles, CA, 90095, USA
| | - Ying Fang
- Department of Microbiology, Immunology & Molecular Genetics, University of California, Los Angeles, CA, 90095, USA
- Department of Bioengineering, University of California, Los Angeles, CA, 90095, USA
| | - Yuning Chen
- Department of Microbiology, Immunology & Molecular Genetics, University of California, Los Angeles, CA, 90095, USA
- Department of Bioengineering, University of California, Los Angeles, CA, 90095, USA
| | - Yan-Ruide Li
- Department of Microbiology, Immunology & Molecular Genetics, University of California, Los Angeles, CA, 90095, USA.
- Department of Bioengineering, University of California, Los Angeles, CA, 90095, USA.
| | - Lili Yang
- Department of Microbiology, Immunology & Molecular Genetics, University of California, Los Angeles, CA, 90095, USA.
- Department of Bioengineering, University of California, Los Angeles, CA, 90095, USA.
- Molecular Biology Institute, University of California, Los Angeles, CA, 90095, USA.
- Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, University of California, Los Angeles, CA, 90095, USA.
- Jonsson Comprehensive Cancer Center, David Geffen School of Medicine, University of California, Los Angeles, CA, 90095, USA.
- Parker Institute for Cancer Immunotherapy, University of California, Los Angeles, CA, 90095, USA.
- Goodman-Luskin Microbiome Center, University of California, Los Angeles, CA, 90095, USA.
| |
Collapse
|
|
2
|
Wilkin C, Piette J, Legrand-Poels S. Unravelling metabolic factors impacting iNKT cell biology in obesity. Biochem Pharmacol 2024; 228:116436. [PMID: 39029630 DOI: 10.1016/j.bcp.2024.116436] [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: 04/26/2024] [Revised: 07/01/2024] [Accepted: 07/15/2024] [Indexed: 07/21/2024]
Abstract
Obesity and related diseases have reached epidemic proportions and continue to rise. Beyond creating an economical burden, obesity and its co-morbidities are associated with shortened human life expectancy. Despite major advances, the underlying mechanisms of obesity remain not fully elucidated. Recently, several studies have highlighted that various immune cells are metabolically reprogrammed in obesity, thereby profoundly affecting the immune system. This sheds light on a new field of interest: the impact of obesity-related systemic metabolic changes affecting immune system that could lead to immunosurveillance loss. Among immune cells altered by obesity, invariant Natural Killer T (iNKT) cells have recently garnered intense focus due to their ability to recognize lipid antigen. While iNKT cells are well-described to be affected by obesity, how and to what extent immunometabolic factors (e.g., lipids, glucose, cytokines, adipokines, insulin and free fatty acids) can drive iNKT cells alterations remains unclear, but represent an emerging field of research. Here, we review the current knowledge on iNKT cells in obesity and discuss the immunometabolic factors that could modulate their phenotype and activity.
Collapse
Affiliation(s)
- Chloé Wilkin
- Laboratory of Immunometabolism and Nutrition, GIGA, ULiège, Liège, Belgium.
| | - Jacques Piette
- Laboratory of Virology and Immunology, GIGA, ULiège, Liège, Belgium
| | | |
Collapse
|
|
3
|
Carriero F, Rubino V, Gelzo M, Scalia G, Raia M, Ciccozzi M, Gentile I, Pinchera B, Castaldo G, Ruggiero G, Terrazzano G. Immune Profile in COVID-19: Unveiling T R3-56 Cells in SARS-CoV-2 Infection. Int J Mol Sci 2024; 25:10465. [PMID: 39408792 PMCID: PMC11477006 DOI: 10.3390/ijms251910465] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2024] [Revised: 09/20/2024] [Accepted: 09/26/2024] [Indexed: 10/20/2024] Open
Abstract
The emergence of COronaVIrus Disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), presented a global health challenge since its identification in December 2019. With clinical manifestations ranging from mild respiratory symptoms to severe multi-organ dysfunction, COVID-19 continues to affect populations worldwide. The complex interactions between SARS-CoV-2 variants and the human immune system are crucial for developing effective therapies, vaccines, and preventive measures. Understanding these immune responses highlights the intricate nature of COVID-19 pathogenesis. This retrospective study analyzed, by flow cytometry approach, a cohort of patients infected with SARS-CoV-2 during the initial pandemic waves from 2020 to 2021. It focused on untreated individuals at the time of hospital admission and examined the presence of TR3-56 cells in their immune profiles during the anti-viral immune response. Our findings provide additional insights into the complex immunological dynamics of SARS-CoV-2 infection and highlight the potential role of TR3-56 cells as crucial components of the immune response. We suggest that TR3-56 cells could serve as valuable biomarkers for identifying more severe cases of COVID-19, aiding in the assessment and management of the disease.
Collapse
Affiliation(s)
- Flavia Carriero
- Dipartimento di Scienze della Salute, Università degli Studi della Basilicata, 85100 Potenza, Italy;
| | - Valentina Rubino
- Dipartimento di Scienze Mediche Traslazionali, Università di Napoli “Federico II”, 80131 Naples, Italy; (V.R.); (G.R.)
| | - Monica Gelzo
- CEINGE-Biotecnologie Avanzate Franco Salvatore, 80131 Naples, Italy; (M.G.); (G.S.); (M.R.); (G.C.)
- Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Università di Napoli Federico II, 80131 Naples, Italy
| | - Giulia Scalia
- CEINGE-Biotecnologie Avanzate Franco Salvatore, 80131 Naples, Italy; (M.G.); (G.S.); (M.R.); (G.C.)
| | - Maddalena Raia
- CEINGE-Biotecnologie Avanzate Franco Salvatore, 80131 Naples, Italy; (M.G.); (G.S.); (M.R.); (G.C.)
| | - Massimo Ciccozzi
- Unità di Epidemiologia e Statistica Medica, Università Campus Biomedico, 00128 Rome, Italy;
| | - Ivan Gentile
- Dipartimento di Medicina Clinica e Chirurgia, Università di Napoli Federico II, 80131 Naples, Italy; (I.G.); (B.P.)
| | - Biagio Pinchera
- Dipartimento di Medicina Clinica e Chirurgia, Università di Napoli Federico II, 80131 Naples, Italy; (I.G.); (B.P.)
| | - Giuseppe Castaldo
- CEINGE-Biotecnologie Avanzate Franco Salvatore, 80131 Naples, Italy; (M.G.); (G.S.); (M.R.); (G.C.)
- Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Università di Napoli Federico II, 80131 Naples, Italy
| | - Giuseppina Ruggiero
- Dipartimento di Scienze Mediche Traslazionali, Università di Napoli “Federico II”, 80131 Naples, Italy; (V.R.); (G.R.)
| | - Giuseppe Terrazzano
- Dipartimento di Scienze della Salute, Università degli Studi della Basilicata, 85100 Potenza, Italy;
| |
Collapse
|
|
4
|
O’Neal J, Mavers M, Jayasinghe RG, DiPersio JF. Traversing the bench to bedside journey for iNKT cell therapies. Front Immunol 2024; 15:1436968. [PMID: 39170618 PMCID: PMC11335525 DOI: 10.3389/fimmu.2024.1436968] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2024] [Accepted: 07/24/2024] [Indexed: 08/23/2024] Open
Abstract
Invariant natural killer T (iNKT) cells are immune cells that harness properties of both the innate and adaptive immune system and exert multiple functions critical for the control of various diseases. Prevention of graft-versus-host disease (GVHD) by iNKT cells has been demonstrated in mouse models and in correlative human studies in which high iNKT cell content in the donor graft is associated with reduced GVHD in the setting of allogeneic hematopoietic stem cell transplants. This suggests that approaches to increase the number of iNKT cells in the setting of an allogeneic transplant may reduce GVHD. iNKT cells can also induce cytolysis of tumor cells, and murine experiments demonstrate that activating iNKT cells in vivo or treating mice with ex vivo expanded iNKT cells can reduce tumor burden. More recently, research has focused on testing anti-tumor efficacy of iNKT cells genetically modified to express a chimeric antigen receptor (CAR) protein (CAR-iNKT) cells to enhance iNKT cell tumor killing. Further, several of these approaches are now being tested in clinical trials, with strong safety signals demonstrated, though efficacy remains to be established following these early phase clinical trials. Here we review the progress in the field relating to role of iNKT cells in GVHD prevention and anti- cancer efficacy. Although the iNKT field is progressing at an exciting rate, there is much to learn regarding iNKT cell subset immunophenotype and functional relationships, optimal ex vivo expansion approaches, ideal treatment protocols, need for cytokine support, and rejection risk of iNKT cells in the allogeneic setting.
Collapse
Affiliation(s)
- Julie O’Neal
- Division of Oncology, Department of Medicine, Washington University School of Medicine, Saint Louis, MO, United States
- Siteman Cancer Center, Washington University in St. Louis, St. Louis, MO, United States
| | - Melissa Mavers
- Siteman Cancer Center, Washington University in St. Louis, St. Louis, MO, United States
- Division of Hematology and Oncology, Department of Pediatrics, Washington University School of Medicine, St. Louis, MO, United States
| | - Reyka G. Jayasinghe
- Division of Oncology, Department of Medicine, Washington University School of Medicine, Saint Louis, MO, United States
| | - John F. DiPersio
- Division of Oncology, Department of Medicine, Washington University School of Medicine, Saint Louis, MO, United States
- Siteman Cancer Center, Washington University in St. Louis, St. Louis, MO, United States
| |
Collapse
|
|
5
|
Carriero F, Rubino V, Leone S, Montanaro R, Brancaleone V, Ruggiero G, Terrazzano G. Regulatory T R3-56 Cells in the Complex Panorama of Immune Activation and Regulation. Cells 2023; 12:2841. [PMID: 38132162 PMCID: PMC10742044 DOI: 10.3390/cells12242841] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2023] [Revised: 12/11/2023] [Accepted: 12/13/2023] [Indexed: 12/23/2023] Open
Abstract
The interplay between immune activation and immune regulation is a fundamental aspect of the functional harmony of the immune system. This delicate balance is essential to triggering correct and effective immune responses against pathogens while preventing excessive inflammation and the immunopathogenic mechanisms of autoimmunity. The knowledge of all the mechanisms involved in immune regulation is not yet definitive, and, probably, the overall picture is much broader than what has been described in the scientific literature so far. Given the plasticity of the immune system and the diversity of organisms, it is highly probable that numerous other cells and molecules are still to be ascribed to the immune regulation process. Here, we report a general overview of how immune activation and regulation interact, based on the involvement of molecules and cells specifically dedicated to these processes. In addition, we discuss the role of TR3-56 lymphocytes as a new cellular candidate in the immune regulation landscape.
Collapse
Affiliation(s)
- Flavia Carriero
- Department of Sciences, University of Basilicata, 85100 Potenza, Italy; (F.C.); (R.M.); (V.B.)
| | - Valentina Rubino
- Department of Translational Medicine, University of Naples Federico II, 80131 Naples, Italy; (V.R.); (G.R.)
| | - Stefania Leone
- Hematopoietic Stem Cell Transplantation Unit, Azienda Ospedaliera A. Cardarelli, 80131 Naples, Italy;
| | - Rosangela Montanaro
- Department of Sciences, University of Basilicata, 85100 Potenza, Italy; (F.C.); (R.M.); (V.B.)
| | - Vincenzo Brancaleone
- Department of Sciences, University of Basilicata, 85100 Potenza, Italy; (F.C.); (R.M.); (V.B.)
| | - Giuseppina Ruggiero
- Department of Translational Medicine, University of Naples Federico II, 80131 Naples, Italy; (V.R.); (G.R.)
| | - Giuseppe Terrazzano
- Department of Sciences, University of Basilicata, 85100 Potenza, Italy; (F.C.); (R.M.); (V.B.)
| |
Collapse
|
|
6
|
Cuño-Gómiz C, de Gregorio E, Tutusaus A, Rider P, Andrés-Sánchez N, Colell A, Morales A, Marí M. Sex-based differences in natural killer T cell-mediated protection against diet-induced steatohepatitis in Balb/c mice. Biol Sex Differ 2023; 14:85. [PMID: 37964320 PMCID: PMC10644614 DOI: 10.1186/s13293-023-00569-w] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/08/2023] [Accepted: 11/06/2023] [Indexed: 11/16/2023] Open
Abstract
BACKGROUND Metabolic dysfunction-associated steatotic liver disease (MASLD) is prevalent in Western countries, evolving into metabolic dysfunction-associated steatohepatitis (MASH) with a sexual dimorphism. Fertile women exhibit lower MASLD risk than men, which diminishes post-menopause. While NKT-cell involvement in steatohepatitis is debated, discrepancies may stem from varied mouse strains used, predominantly C57BL6/J with Th1-dominant responses. Exploration of steatohepatitis, encompassing both genders, using Balb/c background, with Th2-dominant immune response, and CD1d-deficient mice in the Balb/c background (lacking Type I and Type II NKT cells) can clarify gender disparities and NKT-cell influence on MASH progression. METHODS A high fat and choline-deficient (HFCD) diet was used in male and female mice, Balb/c mice or CD1d-/- mice in the Balb/c background that exhibit a Th2-dominant immune response. Liver fibrosis and inflammatory gene expression were measured by qPCR, and histology assessment. NKT cells, T cells, macrophages and neutrophils were assessed by flow cytometry. RESULTS Female mice displayed milder steatohepatitis after 6 weeks of HFCD, showing reduced liver damage, inflammation, and fibrosis compared to males. Male Balb/c mice exhibited NKT-cell protection against steatohepatitis whereas CD1d-/- males on HFCD presented decreased hepatoprotection, increased liver fibrosis, inflammation, neutrophilic infiltration, and inflammatory macrophages. In contrast, the NKT-cell role was negligible in early steatohepatitis development in both female mice, as fibrosis and inflammation were similar despite augmented liver damage in CD1d-/- females. Relevant, hepatic type I NKT levels in female Balb/c mice were significantly lower than in male. CONCLUSIONS NKT cells exert a protective role against experimental steatohepatitis as HFCD-treated CD1d-/- males had more severe fibrosis and inflammation than male Balb/c mice. In females, the HFCD-induced hepatocellular damage and the immune response are less affected by NKT cells on early steatohepatitis progression, underscoring sex-specific NKT-cell influence in MASH development.
Collapse
Affiliation(s)
- Carlos Cuño-Gómiz
- Department of Cell Death and Proliferation, IIBB, CSIC, IDIBAPS, 08036, Barcelona, Spain
- Departament de Biomedicina, Facultat de Medicina, Universitat de Barcelona, 08036, Barcelona, Spain
| | - Estefanía de Gregorio
- Department of Cell Death and Proliferation, IIBB, CSIC, IDIBAPS, 08036, Barcelona, Spain
| | - Anna Tutusaus
- Department of Cell Death and Proliferation, IIBB, CSIC, IDIBAPS, 08036, Barcelona, Spain
| | - Patricia Rider
- Department of Cell Death and Proliferation, IIBB, CSIC, IDIBAPS, 08036, Barcelona, Spain
- Departament de Biomedicina, Facultat de Medicina, Universitat de Barcelona, 08036, Barcelona, Spain
| | - Nuria Andrés-Sánchez
- Institute of Molecular Genetics of Montpellier (IGMM), University of Montpellier, CNRS, INSERM, 34293, Montpellier, France
| | - Anna Colell
- Department of Cell Death and Proliferation, IIBB, CSIC, IDIBAPS, 08036, Barcelona, Spain
| | - Albert Morales
- Department of Cell Death and Proliferation, IIBB, CSIC, IDIBAPS, 08036, Barcelona, Spain.
| | - Montserrat Marí
- Department of Cell Death and Proliferation, IIBB, CSIC, IDIBAPS, 08036, Barcelona, Spain.
| |
Collapse
|
|
7
|
Lee MS, Webb TJ. Novel lipid antigens for NKT cells in cancer. Front Immunol 2023; 14:1173375. [PMID: 37908366 PMCID: PMC10613688 DOI: 10.3389/fimmu.2023.1173375] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2023] [Accepted: 10/02/2023] [Indexed: 11/02/2023] Open
Abstract
Cancer immunotherapy aims to unleash the power of the immune system against tumors without the side effects of traditional chemotherapy. Immunotherapeutic methods vary widely, but all follow the same basic principle: overcome the barriers utilized by cancers to avoid immune destruction. These approaches often revolve around classical T cells, such as with CAR T cells and neoantigen vaccines; however, the utility of the innate-like iNKT cell in cancer immunotherapy has gained significant recognition. iNKT cells parallel classic T cell recognition of peptide antigens presented on MHC through their recognition of lipid antigens presented on the MHC I-like molecule CD1d. Altered metabolism and a lipogenic phenotype are essential properties of tumor cells, representing a unique feature that may be exploited by iNKT cells. In this review, we will cover properties of iNKT cells, CD1d, and lipid antigen presentation. Next, we will discuss the cancer lipidome and how it may be exploited by iNKT cells through a window of opportunity. Finally, we will review, in detail, novel lipid antigens for iNKT cells in cancer.
Collapse
Affiliation(s)
- Michael S. Lee
- Department of Microbiology and Immunology, University of Maryland School of Medicine, Baltimore, MD, United States
- Marlene and Stewart Greenebaum Comprehensive Cancer Center, University of Maryland School of Medicine, Baltimore, MD, United States
| | - Tonya J. Webb
- Department of Microbiology and Immunology, University of Maryland School of Medicine, Baltimore, MD, United States
- Marlene and Stewart Greenebaum Comprehensive Cancer Center, University of Maryland School of Medicine, Baltimore, MD, United States
| |
Collapse
|
|
8
|
Tsumura R, Haruta M, Kuwano M, Yasunaga M. Expansion of mixed immune cells using CD3/CD161 co-stimulation for the treatment of cancer. Sci Rep 2023; 13:6803. [PMID: 37100864 PMCID: PMC10133288 DOI: 10.1038/s41598-023-33987-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2022] [Accepted: 04/21/2023] [Indexed: 04/28/2023] Open
Abstract
Adoptive cell transfer (ACT) is a type of personalized immunotherapy in which expanded immune cells are administered to patients with cancer. However, single-cell populations, such as killer T cells, dendritic cells, natural killer (NK) cells, and NKT (NKT) cells, have been generally used, and their effectiveness remains limited. Here, we established a novel culture method via CD3/CD161 co-stimulation and successfully expanded CD3+/CD4+ helper T cells, CD3+/CD8+ cytotoxic T cells (CTLs), CD3-/CD56+ NK cells, CD3+/CD1d+ NKT cells, CD3+/CD56+ NKT cells, CD3+/TCRγδ+ T cells, and CD3-/CD11c+/HLA-DR+ dendritic cells in peripheral blood mononuclear cells from healthy donors; their respective numbers were 155.5, 1132.5, 5.7, 117.0, 659.2, 325.6, and 6.8 times higher than those before expansion. These mixed immune cells showed strong cytotoxicity against cancer cell lines Capan-1 and SW480. Moreover, both CD3+/CD8+ CTLs and CD3+/CD56+ NKT cells killed tumor cells in cell contact-dependent and -independent manners via granzyme B and interferon-γ/TNF-α, respectively. Furthermore, the cytotoxicity of the mixed cells was significantly superior to that of CTLs or NKTs alone. A bet-hedging CTL-NKT circuitry is one potential mechanism underlying this cooperative cytotoxicity. Collectively, CD3/CD161 co-stimulation may be a promising culture method to expand multiple, distinct immune cell populations for the treatment of cancer.
Collapse
Affiliation(s)
- Ryo Tsumura
- Division of Developmental Therapeutics, EPOC, National Cancer Center, 6-5-1, Kashiwanoha, Kashiwa, Chiba, 277-8577, Japan
| | - Miwa Haruta
- Dojin institute of cancer immunology, Co., Ltd. Kumamoto, Kumamoto, 862-0967, Japan
| | - Masataka Kuwano
- Dojin institute of cancer immunology, Co., Ltd. Kumamoto, Kumamoto, 862-0967, Japan
| | - Masahiro Yasunaga
- Division of Developmental Therapeutics, EPOC, National Cancer Center, 6-5-1, Kashiwanoha, Kashiwa, Chiba, 277-8577, Japan.
| |
Collapse
|
|
9
|
Almeida JS, Casanova JM, Santos-Rosa M, Tarazona R, Solana R, Rodrigues-Santos P. Natural Killer T-like Cells: Immunobiology and Role in Disease. Int J Mol Sci 2023; 24:ijms24032743. [PMID: 36769064 PMCID: PMC9917533 DOI: 10.3390/ijms24032743] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2023] [Revised: 01/27/2023] [Accepted: 01/29/2023] [Indexed: 02/04/2023] Open
Abstract
CD56+ T cells are generally recognized as a distinct population of T cells and are categorized as NKT-like cells. Although our understanding of NKT-like cells is far from satisfactory, it has been shown that aging and a number of disease situations have impacted these cells. To construct an overview of what is currently known, we reviewed the literature on human NKT-like cells. NKT-like cells are highly differentiated T cells with "CD1d-independent" antigen recognition and MHC-unrestricted cell killing. The genesis of NKT-like cells is unclear; however, it is proposed that the acquisition of innate characteristics by T cells could represent a remodeling process leading to successful aging. Additionally, it has been shown that NKT-like cells may play a significant role in several pathological conditions, making it necessary to comprehend whether these cells might function as prognostic markers. The quantification and characterization of these cells might serve as a cutting-edge indicator of individual immune health. Additionally, exploring the mechanisms that can control their killing activity in different contexts may therefore result in innovative therapeutic alternatives in a wide range of disease settings.
Collapse
Affiliation(s)
- Jani-Sofia Almeida
- Institute of Immunology, Faculty of Medicine, University of Coimbra (FMUC), 3004-504 Coimbra, Portugal
- Laboratory of Immunology and Oncology, Center for Neuroscience and Cell Biology (CNC), University of Coimbra, 3004-504 Coimbra, Portugal
- Center of Investigation in Environment, Genetics and Oncobiology (CIMAGO), Faculty of Medicine, University of Coimbra, 3004-504 Coimbra, Portugal
- Coimbra Institute for Clinical and Biomedical Research (iCBR), Faculty of Medicine, University of Coimbra, 3000-548 Coimbra, Portugal
- Center for Innovation in Biomedicine and Biotechnology (CIBB), University of Coimbra, 3004-504 Coimbra, Portugal
- Clinical Academic Centre of Coimbra (CACC), 3000-075 Coimbra, Portugal
| | - José Manuel Casanova
- Center of Investigation in Environment, Genetics and Oncobiology (CIMAGO), Faculty of Medicine, University of Coimbra, 3004-504 Coimbra, Portugal
- Coimbra Institute for Clinical and Biomedical Research (iCBR), Faculty of Medicine, University of Coimbra, 3000-548 Coimbra, Portugal
- Center for Innovation in Biomedicine and Biotechnology (CIBB), University of Coimbra, 3004-504 Coimbra, Portugal
- Clinical Academic Centre of Coimbra (CACC), 3000-075 Coimbra, Portugal
- University Clinic of Orthopedics, Orthopedics Service, Tumor Unit of the Locomotor Apparatus (UTAL), Coimbra Hospital and Universitary Center (CHUC), 3000-075 Coimbra, Portugal
| | - Manuel Santos-Rosa
- Institute of Immunology, Faculty of Medicine, University of Coimbra (FMUC), 3004-504 Coimbra, Portugal
- Center of Investigation in Environment, Genetics and Oncobiology (CIMAGO), Faculty of Medicine, University of Coimbra, 3004-504 Coimbra, Portugal
- Coimbra Institute for Clinical and Biomedical Research (iCBR), Faculty of Medicine, University of Coimbra, 3000-548 Coimbra, Portugal
- Center for Innovation in Biomedicine and Biotechnology (CIBB), University of Coimbra, 3004-504 Coimbra, Portugal
- Clinical Academic Centre of Coimbra (CACC), 3000-075 Coimbra, Portugal
| | - Raquel Tarazona
- Immunology Unit, Department of Physiology, University of Extremadura, 10003 Cáceres, Spain
| | - Rafael Solana
- Maimonides Biomedical Research Institute of Cordoba (IMIBIC), Reina Sofía University Hospital, 14004 Córdoba, Spain
- Immunology Unit, Department of Cell Biology, Physiology and Immunology, University of Córdoba, 14071 Córdoba, Spain
| | - Paulo Rodrigues-Santos
- Institute of Immunology, Faculty of Medicine, University of Coimbra (FMUC), 3004-504 Coimbra, Portugal
- Laboratory of Immunology and Oncology, Center for Neuroscience and Cell Biology (CNC), University of Coimbra, 3004-504 Coimbra, Portugal
- Center of Investigation in Environment, Genetics and Oncobiology (CIMAGO), Faculty of Medicine, University of Coimbra, 3004-504 Coimbra, Portugal
- Coimbra Institute for Clinical and Biomedical Research (iCBR), Faculty of Medicine, University of Coimbra, 3000-548 Coimbra, Portugal
- Center for Innovation in Biomedicine and Biotechnology (CIBB), University of Coimbra, 3004-504 Coimbra, Portugal
- Clinical Academic Centre of Coimbra (CACC), 3000-075 Coimbra, Portugal
- Correspondence:
| |
Collapse
|
|
10
|
Antitumor Immunity Exerted by Natural Killer and Natural Killer T Cells in the Liver. J Clin Med 2023; 12:jcm12030866. [PMID: 36769513 PMCID: PMC9917438 DOI: 10.3390/jcm12030866] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2022] [Revised: 01/10/2023] [Accepted: 01/19/2023] [Indexed: 01/24/2023] Open
Abstract
The liver plays crucial roles in systemic immunity and greatly contributes to the systemic defense mechanism. Antitumor immunity in the liver is especially critical for the defense against systemic tumor cell dissemination. To achieve effective defense against metastatic tumor cells, liver immune cells with powerful cytotoxic activities construct a potent defense mechanism. In the liver, as compared with other organs, there is a significantly more intense percentage of innate immune lymphocytes, such as natural killer (NK) and NKT cells. These characteristic lymphocytes survey the portal blood transferred to the liver from the alimentary tract and eliminate malignant cells with their robust cytotoxic ability. Additionally, with their active cytokine-producing capacity, these innate lymphocytes initiate immunological sequences by adaptive immune cells. Therefore, they are crucial contributors to systemic antitumor immunity. These attractive immune cells help conduct a fundamental investigation of tumor immunity and act as a target of clinical measures for cancer therapies. This review discusses the mechanisms of these innate lymphocytes regarding recognition and cytotoxicity against tumor cells and the possibility of clinical applications for therapeutic measures.
Collapse
|
|
11
|
Tang S, Wang Y, Ma X, Xiang X, Zhou X, Li Y, Jia Y, Hu F, Li Y. Decreased natural killer T-like cells correlated to disease activity in systemic lupus erythematosus. Clin Rheumatol 2023; 42:1435-1442. [PMID: 36629999 DOI: 10.1007/s10067-022-06494-4] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2022] [Revised: 11/30/2022] [Accepted: 12/23/2022] [Indexed: 01/12/2023]
Abstract
OBJECTIVES To evaluate the absolute numbers and frequencies of natural killer T-like (NKT-like) cells in systemic lupus erythematosus (SLE) and to characterize the possible role of the cells. METHODS Seventy-nine patients with SLE together with 30 age- and sex-matched healthy controls were enrolled. Flow cytometric determination of peripheral NKT-like cells was carried out for all participants by detecting the absolute counts (Abs) and percentage (%) of CD3 + CD16 + CD56 + cells. Disease activity index, laboratory parameters, and clinical manifestations were collected. The correlation between the cells and these parameters was analyzed. RESULTS SLE patients had, with respect to controls, considerably decreased values of NKT-like cells (P < 0.001 in both absolute number and percentage). The absolute number of NKT-like cells was found to have positive correlations with WBC, RBC, PLT, C3, C4, IgM and negative correlations with the disease duration, SLEDAI-2 K, anti-dsDNA, anti-nucleosome, anti-ribosomal protein, CRP, ESR. Meanwhile, it was found that the percentage values of NKT-like cells decreased in SLE patients with nephritis which was correlated with anti-ribosomal protein and CRP in comparison to SLE patients without nephritis. Moreover, an increase in the NKT-like cell counts was also observed in the patients with a clinical response to the treatment. CONCLUSIONS The absolute counts and frequencies of NKT-like cells decreased in SLE patients significantly, which correlated to disease activities and could recover to normal after the treatment. The NKT-like cells may play an important role in the pathogenesis of SLE and could be a useful marker in the disease assessment. Key Points • The absolute counts and frequencies of NKT-like cells decreased in SLE patients significantly. • NKT-like cells were related to the disease activities and could restore after the treatment. • NKT-like cells may be a useful marker in the disease assessment.
Collapse
Affiliation(s)
- Sumei Tang
- Department of Rheumatology and Immunology, Peking University People's Hospital & Beijing Key Laboratory for Rheumatism Mechanism and Immune Diagnosis (BZ0135), 11 Xizhimen South St, Beijing, 100044, China
| | - Yushu Wang
- Inspection Center, Qingdao University Medical College Affiliated Yantai Yuhuangding Hospital, Yantai, 264000, China
| | - Xiangbo Ma
- Department of Rheumatology and Immunology, Handan First Hospital, Hebei, China
| | - Xiaohong Xiang
- Department of Rheumatology and Immunology, Peking University People's Hospital & Beijing Key Laboratory for Rheumatism Mechanism and Immune Diagnosis (BZ0135), 11 Xizhimen South St, Beijing, 100044, China
| | - Xinhua Zhou
- Clinical Laboratory, Third Hospital of Nanchang, Jiangxi, 330009, China
| | - Yan Li
- Clinical Laboratory, First People's Hospital of Jinzhong, Shanxi, 030600, China
| | - Yuan Jia
- Department of Rheumatology and Immunology, Peking University People's Hospital & Beijing Key Laboratory for Rheumatism Mechanism and Immune Diagnosis (BZ0135), 11 Xizhimen South St, Beijing, 100044, China
| | - Fanlei Hu
- Department of Rheumatology and Immunology, Peking University People's Hospital & Beijing Key Laboratory for Rheumatism Mechanism and Immune Diagnosis (BZ0135), 11 Xizhimen South St, Beijing, 100044, China.
| | - Yingni Li
- Department of Rheumatology and Immunology, Peking University People's Hospital & Beijing Key Laboratory for Rheumatism Mechanism and Immune Diagnosis (BZ0135), 11 Xizhimen South St, Beijing, 100044, China.
| |
Collapse
|
|
12
|
Kratzmeier C, Singh S, Asiedu EB, Webb TJ. Current Developments in the Preclinical and Clinical use of Natural Killer T cells. BioDrugs 2023; 37:57-71. [PMID: 36525216 PMCID: PMC9756707 DOI: 10.1007/s40259-022-00572-4] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 11/26/2022] [Indexed: 12/23/2022]
Abstract
Natural killer T (NKT) cells play a pivotal role as a bridge between the innate and the adaptive immune response and are instrumental in the regulation of homeostasis. In this review, we discuss the potential for NKT cells to serve as biodrugs in viral infections and in cancer. NKT cells are being investigated for their use as a prognostic biomarker, an immune adjuvant, and as a form of cellular therapy. Historically, the clinical utility of NKT cells was hampered by their low frequency in the blood, discrepancies in nomenclature, and challenges with ex vivo expansion. However, recent advances in the field have permitted the development of several NKT cell-based preclinical and clinical strategies. These new developments pave the way for the successful implementation of NKT cell-based approaches for the treatment of human disease.
Collapse
Affiliation(s)
- Christina Kratzmeier
- Department of Microbiology and Immunology, and the Marlene and Stewart Greenebaum Comprehensive Cancer Center, University of Maryland School of Medicine, 685 West Baltimore St, HSF I-Room 380, Baltimore, MD, 21201, USA
| | - Sasha Singh
- Department of Microbiology and Immunology, and the Marlene and Stewart Greenebaum Comprehensive Cancer Center, University of Maryland School of Medicine, 685 West Baltimore St, HSF I-Room 380, Baltimore, MD, 21201, USA
| | - Emmanuel B Asiedu
- Department of Microbiology and Immunology, and the Marlene and Stewart Greenebaum Comprehensive Cancer Center, University of Maryland School of Medicine, 685 West Baltimore St, HSF I-Room 380, Baltimore, MD, 21201, USA
| | - Tonya J Webb
- Department of Microbiology and Immunology, and the Marlene and Stewart Greenebaum Comprehensive Cancer Center, University of Maryland School of Medicine, 685 West Baltimore St, HSF I-Room 380, Baltimore, MD, 21201, USA.
| |
Collapse
|
|
13
|
Gu X, Chu Q, Ma X, Wang J, Chen C, Guan J, Ren Y, Wu S, Zhu H. New insights into iNKT cells and their roles in liver diseases. Front Immunol 2022; 13:1035950. [PMID: 36389715 PMCID: PMC9643775 DOI: 10.3389/fimmu.2022.1035950] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2022] [Accepted: 10/14/2022] [Indexed: 08/29/2023] Open
Abstract
Natural killer T cells (NKTs) are an important part of the immune system. Since their discovery in the 1990s, researchers have gained deeper insights into the physiology and functions of these cells in many liver diseases. NKT cells are divided into two subsets, type I and type II. Type I NKT cells are also named iNKT cells as they express a semi-invariant T cell-receptor (TCR) α chain. As part of the innate immune system, hepatic iNKT cells interact with hepatocytes, macrophages (Kupffer cells), T cells, and dendritic cells through direct cell-to-cell contact and cytokine secretion, bridging the innate and adaptive immune systems. A better understanding of hepatic iNKT cells is necessary for finding new methods of treating liver disease including autoimmune liver diseases, alcoholic liver diseases (ALDs), non-alcoholic fatty liver diseases (NAFLDs), and liver tumors. Here we summarize how iNKT cells are activated, how they interact with other cells, and how they function in the presence of liver disease.
Collapse
Affiliation(s)
- Xinyu Gu
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Qingfei Chu
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Xiao Ma
- Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
| | - Jing Wang
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Chao Chen
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Jun Guan
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Yanli Ren
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Shanshan Wu
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Haihong Zhu
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| |
Collapse
|
|
14
|
Larsen SE, Williams BD, Rais M, Coler RN, Baldwin SL. It Takes a Village: The Multifaceted Immune Response to Mycobacterium tuberculosis Infection and Vaccine-Induced Immunity. Front Immunol 2022; 13:840225. [PMID: 35359957 PMCID: PMC8960931 DOI: 10.3389/fimmu.2022.840225] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2021] [Accepted: 02/08/2022] [Indexed: 11/18/2022] Open
Abstract
Despite co-evolving with humans for centuries and being intensely studied for decades, the immune correlates of protection against Mycobacterium tuberculosis (Mtb) have yet to be fully defined. This lapse in understanding is a major lag in the pipeline for evaluating and advancing efficacious vaccine candidates. While CD4+ T helper 1 (TH1) pro-inflammatory responses have a significant role in controlling Mtb infection, the historically narrow focus on this cell population may have eclipsed the characterization of other requisite arms of the immune system. Over the last decade, the tuberculosis (TB) research community has intentionally and intensely increased the breadth of investigation of other immune players. Here, we review mechanistic preclinical studies as well as clinical anecdotes that suggest the degree to which different cell types, such as NK cells, CD8+ T cells, γ δ T cells, and B cells, influence infection or disease prevention. Additionally, we categorically outline the observed role each major cell type plays in vaccine-induced immunity, including Mycobacterium bovis bacillus Calmette-Guérin (BCG). Novel vaccine candidates advancing through either the preclinical or clinical pipeline leverage different platforms (e.g., protein + adjuvant, vector-based, nucleic acid-based) to purposefully elicit complex immune responses, and we review those design rationales and results to date. The better we as a community understand the essential composition, magnitude, timing, and trafficking of immune responses against Mtb, the closer we are to reducing the severe disease burden and toll on human health inflicted by TB globally.
Collapse
Affiliation(s)
- Sasha E. Larsen
- Center for Global Infectious Disease Research, Seattle Children's Research Institute, Seattle Children's Hospital, Seattle, WA, United States
| | - Brittany D. Williams
- Center for Global Infectious Disease Research, Seattle Children's Research Institute, Seattle Children's Hospital, Seattle, WA, United States,Department of Global Health, University of Washington, Seattle, WA, United States
| | - Maham Rais
- Center for Global Infectious Disease Research, Seattle Children's Research Institute, Seattle Children's Hospital, Seattle, WA, United States
| | - Rhea N. Coler
- Center for Global Infectious Disease Research, Seattle Children's Research Institute, Seattle Children's Hospital, Seattle, WA, United States,Department of Global Health, University of Washington, Seattle, WA, United States,Department of Pediatrics, University of Washington School of Medicine, Seattle, WA, United States
| | - Susan L. Baldwin
- Center for Global Infectious Disease Research, Seattle Children's Research Institute, Seattle Children's Hospital, Seattle, WA, United States,*Correspondence: Susan L. Baldwin,
| |
Collapse
|
|
15
|
Li Y, Sharma A, Maciaczyk J, Schmidt-Wolf IGH. Recent Development in NKT-Based Immunotherapy of Glioblastoma: From Bench to Bedside. Int J Mol Sci 2022; 23:ijms23031311. [PMID: 35163235 PMCID: PMC8835986 DOI: 10.3390/ijms23031311] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2021] [Revised: 01/15/2022] [Accepted: 01/20/2022] [Indexed: 02/07/2023] Open
Abstract
Glioblastoma multiforme (GBM) is an aggressive and dismal disease with a median overall survival of around 15 months and a 5-year survival rate of 7.2%. Owing to genetic mutations, drug resistance, disruption to the blood–brain barrier (BBB)/blood–brain tumor barrier (BBTB), and the complexity of the immunosuppressive environment, the therapeutic approaches to GBM represent still major challenges. Conventional therapies, including surgery, radiotherapy, and standard chemotherapy with temozolomide, have not resulted in satisfactory improvements in the overall survival of GBM patients. Among cancer immunotherapeutic approaches, we propose that adjuvant NKT immunotherapy with invariant NKT (iNKT) and cytokine-induced killer (CIK) cells may improve the clinical scenario of this devastating disease. Considering this, herein, we discuss the current strategies of NKT therapy for GBM based primarily on in vitro/in vivo experiments, clinical trials, and the combinatorial approaches with future therapeutic potential.
Collapse
Affiliation(s)
- Yutao Li
- Center for Integrated Oncology (CIO), Department of Integrated Oncology, University Hospital Bonn, 53127 Bonn, Germany;
| | - Amit Sharma
- Department of Neurosurgery, University Hospital Bonn, 53127 Bonn, Germany; (A.S.); (J.M.)
| | - Jarek Maciaczyk
- Department of Neurosurgery, University Hospital Bonn, 53127 Bonn, Germany; (A.S.); (J.M.)
- Department of Surgical Sciences, University of Otago, Dunedin 9054, New Zealand
| | - Ingo G. H. Schmidt-Wolf
- Center for Integrated Oncology (CIO), Department of Integrated Oncology, University Hospital Bonn, 53127 Bonn, Germany;
- Correspondence: ; Tel.: +49-228-2871-7050
| |
Collapse
|
|
16
|
Cairo C, Webb TJ. Effective Barriers: The Role of NKT Cells and Innate Lymphoid Cells in the Gut. JOURNAL OF IMMUNOLOGY (BALTIMORE, MD. : 1950) 2022; 208:235-246. [PMID: 35017213 DOI: 10.4049/jimmunol.2100799] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/13/2021] [Accepted: 10/19/2021] [Indexed: 06/14/2023]
Abstract
The critical role of commensal microbiota in regulating the host immune response has been established. In addition, it is known that host-microbial interactions are bidirectional, and this interplay is tightly regulated to prevent chronic inflammatory disease. Although many studies have focused on the role of classic T cell subsets, unconventional lymphocytes such as NKT cells and innate lymphoid cells also contribute to the regulation of homeostasis at mucosal surfaces and influence the composition of the intestinal microbiota. In this review, we discuss the mechanisms involved in the cross-regulation between NKT cells, innate lymphoid cells, and the gut microbiota. Moreover, we highlight how disruptions in homeostasis can lead to immune-mediated disorders.
Collapse
Affiliation(s)
- Cristiana Cairo
- Department of Medicine, University of Maryland School of Medicine, Baltimore, MD;
- Institute of Human Virology, University of Maryland School of Medicine, Baltimore, MD
| | - Tonya J Webb
- Department of Microbiology and Immunology, University of Maryland School of Medicine, Baltimore, MD; and
- Marlene and Stewart Greenebaum Comprehensive Cancer Center, University of Maryland School of Medicine, Baltimore, MD
| |
Collapse
|
|
17
|
Miller D, Motomura K, Galaz J, Gershater M, Lee ED, Romero R, Gomez-Lopez N. Cellular immune responses in the pathophysiology of preeclampsia. J Leukoc Biol 2022; 111:237-260. [PMID: 33847419 PMCID: PMC8511357 DOI: 10.1002/jlb.5ru1120-787rr] [Citation(s) in RCA: 60] [Impact Index Per Article: 20.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2023] Open
Abstract
Preeclampsia, defined as new-onset hypertension accompanied by proteinuria occurring at 20 weeks of gestation or later, is a leading cause of perinatal morbidity and mortality worldwide. The pathophysiology of this major multi-systemic syndrome includes defective deep placentation, oxidative stress, endothelial dysfunction, the presence of an anti-angiogenic state, and intravascular inflammation, among others. In this review, we provide a comprehensive overview of the cellular immune responses involved in the pathogenesis of preeclampsia. Specifically, we summarize the role of innate and adaptive immune cells in the maternal circulation, reproductive tissues, and at the maternal-fetal interface of women affected by this pregnancy complication. The major cellular subsets involved in the pathogenesis of preeclampsia are regulatory T cells, effector T cells, NK cells, monocytes, macrophages, and neutrophils. We also summarize the literature on those immune cells that have been less characterized in this clinical condition, such as γδ T cells, invariant natural killer T cells, dendritic cells, mast cells, and B cells. Moreover, we discuss in vivo studies utilizing a variety of animal models of preeclampsia to further support the role of immune cells in this disease. Finally, we highlight the existing gaps in knowledge of the immunobiology of preeclampsia that require further investigation. The goal of this review is to promote translational research leading to clinically relevant strategies that can improve adverse perinatal outcomes resulting from the obstetrical syndrome of preeclampsia.
Collapse
Affiliation(s)
- Derek Miller
- Perinatology Research Branch, Division of Obstetrics and Maternal-Fetal Medicine, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, U.S. Department of Health and Human Services (NICHD/NIH/DHHS); Bethesda, Maryland, and Detroit, Michigan, USA
- Department of Obstetrics and Gynecology, Wayne State University School of Medicine, Detroit, Michigan, USA
| | - Kenichiro Motomura
- Perinatology Research Branch, Division of Obstetrics and Maternal-Fetal Medicine, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, U.S. Department of Health and Human Services (NICHD/NIH/DHHS); Bethesda, Maryland, and Detroit, Michigan, USA
- Department of Obstetrics and Gynecology, Wayne State University School of Medicine, Detroit, Michigan, USA
| | - Jose Galaz
- Perinatology Research Branch, Division of Obstetrics and Maternal-Fetal Medicine, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, U.S. Department of Health and Human Services (NICHD/NIH/DHHS); Bethesda, Maryland, and Detroit, Michigan, USA
- Department of Obstetrics and Gynecology, Wayne State University School of Medicine, Detroit, Michigan, USA
| | - Meyer Gershater
- Perinatology Research Branch, Division of Obstetrics and Maternal-Fetal Medicine, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, U.S. Department of Health and Human Services (NICHD/NIH/DHHS); Bethesda, Maryland, and Detroit, Michigan, USA
- Department of Obstetrics and Gynecology, Wayne State University School of Medicine, Detroit, Michigan, USA
| | - Eun D. Lee
- Department of Microbiology and Immunology, Virginia Commonwealth University, Richmond, Virginia, USA
- Department of Obstetrics and Gynecology, Virginia Commonwealth University, Richmond, Virginia, USA
| | - Roberto Romero
- Perinatology Research Branch, Division of Obstetrics and Maternal-Fetal Medicine, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, U.S. Department of Health and Human Services (NICHD/NIH/DHHS); Bethesda, Maryland, and Detroit, Michigan, USA
- Department of Obstetrics and Gynecology, University of Michigan, Ann Arbor, Michigan, USA
- Department of Epidemiology and Biostatistics, Michigan State University, East Lansing, Michigan, USA
- Center for Molecular Medicine and Genetics, Wayne State University, Detroit, Michigan, USA
- Detroit Medical Center, Detroit, Michigan, USA
- Department of Obstetrics and Gynecology, Florida International University, Miami, Florida, USA
| | - Nardhy Gomez-Lopez
- Perinatology Research Branch, Division of Obstetrics and Maternal-Fetal Medicine, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, U.S. Department of Health and Human Services (NICHD/NIH/DHHS); Bethesda, Maryland, and Detroit, Michigan, USA
- Department of Obstetrics and Gynecology, Wayne State University School of Medicine, Detroit, Michigan, USA
- Department of Biochemistry, Microbiology, and Immunology, Wayne State University School of Medicine, Detroit, Michigan, USA
| |
Collapse
|
|
18
|
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: 274] [Impact Index Per Article: 68.5] [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.
Collapse
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
| |
Collapse
|
|
19
|
Nelson A, Lukacs JD, Johnston B. The Current Landscape of NKT Cell Immunotherapy and the Hills Ahead. Cancers (Basel) 2021; 13:cancers13205174. [PMID: 34680322 PMCID: PMC8533824 DOI: 10.3390/cancers13205174] [Citation(s) in RCA: 74] [Impact Index Per Article: 18.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2021] [Revised: 10/05/2021] [Accepted: 10/05/2021] [Indexed: 12/15/2022] Open
Abstract
Simple Summary Natural killer T (NKT) cells are a subset of lipid-reactive T cells that enhance anti-tumor immunity. While preclinical studies have shown NKT cell immunotherapy to be safe and effective, clinical studies lack predictable therapeutic efficacy and no approved treatments exist. In this review, we outline the current strategies, challenges, and outlook for NKT cell immunotherapy. Abstract NKT cells are a specialized subset of lipid-reactive T lymphocytes that play direct and indirect roles in immunosurveillance and anti-tumor immunity. Preclinical studies have shown that NKT cell activation via delivery of exogenous glycolipids elicits a significant anti-tumor immune response. Furthermore, infiltration of NKT cells is associated with a good prognosis in several cancers. In this review, we aim to summarize the role of NKT cells in cancer as well as the current strategies and status of NKT cell immunotherapy. This review also examines challenges and future directions for improving the therapy.
Collapse
Affiliation(s)
- Adam Nelson
- Department of Microbiology and Immunology, Dalhousie University, Halifax, NS B3H 4R2, Canada; (A.N.); (J.D.L.)
- Beatrice Hunter Cancer Research Institute, Halifax, NS B3H 4R2, Canada
| | - Jordan D. Lukacs
- Department of Microbiology and Immunology, Dalhousie University, Halifax, NS B3H 4R2, Canada; (A.N.); (J.D.L.)
- Beatrice Hunter Cancer Research Institute, Halifax, NS B3H 4R2, Canada
| | - Brent Johnston
- Department of Microbiology and Immunology, Dalhousie University, Halifax, NS B3H 4R2, Canada; (A.N.); (J.D.L.)
- Beatrice Hunter Cancer Research Institute, Halifax, NS B3H 4R2, Canada
- Department of Pediatrics, Dalhousie University, Halifax, NS B3H 4R2, Canada
- Department of Pathology, Dalhousie University, Halifax, NS B3H 4R2, Canada
- Correspondence:
| |
Collapse
|
|
20
|
Bai X, Wang N, Zhou J, Cui M, Jing X, Liu N. DX5 + NKT cells' increase was correlated with liver damage in FVB mice not in BALB/c mice infected by Clonorchis sinensis. Parasite Immunol 2020; 43:e12796. [PMID: 32984976 DOI: 10.1111/pim.12796] [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: 04/20/2020] [Revised: 09/16/2020] [Accepted: 09/21/2020] [Indexed: 12/26/2022]
Abstract
AIMS DX5+ NKT cells' distribution and population change in BALB/c and FVB mice infected by C sinensis and their function in liver damage were investigated. METHODS AND RESULTS Mice were infected by Clonorchis sinensis metacercariae, and lymphocytes were isolated from the livers, spleens and peripheral blood. NK, DX5+ NKT, INF-γ+ DX5+ NKT cells and liver fibrosis were analysed. The DX5+ NKT cells displayed the largest amount in normal BALB/c mice liver followed by peripheral blood and spleen. Although the hepatic DX5+ NKT cells of BALB/c mice were more than that of FVB mice, they did not show significant percentage change after C sinensis infection. The hepatic DX5+ NKT cells of FVB mice increased remarkably after infection accompanied with heavier liver injury and fibrosis than the BALB/c mice. And hydroxyproline content was also positively correlated with DX5+ NKT cells only in FVB mice. However, the increase of IFN-γ producing DX5+ NKT cells was lower in FVB mice than in BALB/c mice which showed sharp increase with mild liver damage after infection. The frequencies of anti-fibrotic NK cells were similar in both of the two mouse strains. CONCLUSIONS C sinensis could induce different DX5+ NKT cells responses in different mouse strains which may play roles in liver injury and fibrosis in FVB mice.
Collapse
Affiliation(s)
- Xuelian Bai
- Clinical Medicine Laboratory, Binzhou Medical University Hospital, Binzhou, China
| | - Nan Wang
- Clinical Medicine Laboratory, Binzhou Medical University Hospital, Binzhou, China
| | - Jie Zhou
- Clinical Medicine Laboratory, Binzhou Medical University Hospital, Binzhou, China
| | - Min Cui
- Department of Pediatrics, Binzhou City People's Hospital, Binzhou, China
| | - Xuening Jing
- Department of Immunology, Shandong College of Traditional Chinese Medicine, Yantai, China
| | - Naiguo Liu
- Clinical Medicine Laboratory, Binzhou Medical University Hospital, Binzhou, China
| |
Collapse
|
|
21
|
Driver JP, de Carvalho Madrid DM, Gu W, Artiaga BL, Richt JA. Modulation of Immune Responses to Influenza A Virus Vaccines by Natural Killer T Cells. Front Immunol 2020; 11:2172. [PMID: 33193296 PMCID: PMC7606973 DOI: 10.3389/fimmu.2020.02172] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2020] [Accepted: 08/10/2020] [Indexed: 12/20/2022] Open
Abstract
Influenza A viruses (IAVs) circulate widely among different mammalian and avian hosts and sometimes give rise to zoonotic infections. Vaccination is a mainstay of IAV prevention and control. However, the efficacy of IAV vaccines is often suboptimal because of insufficient cross-protection among different IAV genotypes and subtypes as well as the inability to keep up with the rapid molecular evolution of IAV strains. Much attention is focused on improving IAV vaccine efficiency using adjuvants, which are substances that can modulate and enhance immune responses to co-administered antigens. The current review is focused on a non-traditional approach of adjuvanting IAV vaccines by therapeutically targeting the immunomodulatory functions of a rare population of innate-like T lymphocytes called invariant natural killer T (iNKT) cells. These cells bridge the innate and adaptive immune systems and are capable of stimulating a wide array of immune cells that enhance vaccine-mediated immune responses. Here we discuss the factors that influence the adjuvant effects of iNKT cells for influenza vaccines as well as the obstacles that must be overcome before this novel adjuvant approach can be considered for human or veterinary use.
Collapse
Affiliation(s)
- John P Driver
- Department of Animal Sciences, University of Florida, Gainesville, FL, United States
| | | | - Weihong Gu
- Department of Animal Sciences, University of Florida, Gainesville, FL, United States
| | - Bianca L Artiaga
- Diagnostic Medicine/Pathobiology, College of Veterinary Medicine, Kansas State University, Manhattan, KS, United States
| | - Jürgen A Richt
- Diagnostic Medicine/Pathobiology, College of Veterinary Medicine, Kansas State University, Manhattan, KS, United States
| |
Collapse
|
|
22
|
Chen D, Zhao H, Gao X, Chen S, Liu H, Zhang J, Zhang J, Meng M. Subcutaneous administration of α-GalCer activates iNKT10 cells to promote M2 macrophage polarization and ameliorates chronic inflammation of obese adipose tissue. Int Immunopharmacol 2019; 77:105948. [PMID: 31629216 DOI: 10.1016/j.intimp.2019.105948] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2019] [Revised: 09/13/2019] [Accepted: 09/27/2019] [Indexed: 12/25/2022]
Abstract
OBJECTIVE The role of iNKT cells was investigated in chronic adipose tissue inflammation in obese mice after administration of α-GalCer in different pathways. METHODS C57BL/6J mice were fed high-fat diet (HFD) for 12 weeks to establish the obese mouse model. The pathology of adipose tissue was observed by H&E staining. The rates of iNKT cells, macrophages and cell subsets in adipose tissue were detected by FCM. Cytokine levels in serum and adipose tissue lymphocyte-stimulated supernatants were assessed with the CBA kit. The expression levels of related transcription factor in adipose tissue were detected by Western blot. RESULTS The proportions of iNKT cells, iNKT10 cells and M2 macrophages were decreased, while those of iNKT1 and M1 macrophages were increased in adipose tissue of HFD-fed mice. The expression levels of the related transcriptional proteins E4BP4 and Arg-1 were decreased while iNOS expression was increased in adipose tissue. Administration of α-GalCer by subcutaneous injection resulted in increased rates of iNKT10 cells and M2 macrophages, and decreased amounts of M1 macrophages in adipose tissue of HFD-fed mice. The expression of E4BP4 and Arg-1 were up-regulated, but iNOS was down-regulated. Meanwhile, infiltration of inflammatory cells into adipose tissue was further reduced. CONCLUSION The imbalance between the proportions of iNKT1 and iNKT10 cells may be involved in the development of chronic inflammation in obese adipose tissue. Administration of α-GalCer by subcutaneous injection in HFD-fed mice activates adipose tissue iNKT10 cells, which promote M2 macrophage polarization and improve chronic inflammation in obese adipose tissue.
Collapse
Affiliation(s)
- Dongzhi Chen
- Department of Immunology, School of Medicine, Hebei University, Baoding 071000, Hebei Province, PR China; Key Laboratory of Pathogenesis Mechanism and Control of Inflammatory-autoimmune Diseases in Hebei Province, Baoding, PR China
| | - Huijuan Zhao
- Department of Immunology, School of Medicine, Hebei University, Baoding 071000, Hebei Province, PR China; Key Laboratory of Pathogenesis Mechanism and Control of Inflammatory-autoimmune Diseases in Hebei Province, Baoding, PR China
| | - Xiang Gao
- Department of Immunology, School of Medicine, Hebei University, Baoding 071000, Hebei Province, PR China; Key Laboratory of Pathogenesis Mechanism and Control of Inflammatory-autoimmune Diseases in Hebei Province, Baoding, PR China
| | - Shengde Chen
- Department of Immunology, School of Medicine, Hebei University, Baoding 071000, Hebei Province, PR China; Key Laboratory of Pathogenesis Mechanism and Control of Inflammatory-autoimmune Diseases in Hebei Province, Baoding, PR China
| | - Huifang Liu
- Department of Immunology, School of Medicine, Hebei University, Baoding 071000, Hebei Province, PR China; Key Laboratory of Pathogenesis Mechanism and Control of Inflammatory-autoimmune Diseases in Hebei Province, Baoding, PR China
| | - Jingnan Zhang
- Department of Immunology, School of Medicine, Hebei University, Baoding 071000, Hebei Province, PR China; Key Laboratory of Pathogenesis Mechanism and Control of Inflammatory-autoimmune Diseases in Hebei Province, Baoding, PR China
| | - Jinku Zhang
- Department of Pathology, The First Centre Hospital of Baoding, Baoding, Hebei Province, PR China
| | - Ming Meng
- Department of Immunology, School of Medicine, Hebei University, Baoding 071000, Hebei Province, PR China; Key Laboratory of Pathogenesis Mechanism and Control of Inflammatory-autoimmune Diseases in Hebei Province, Baoding, PR China.
| |
Collapse
|
|
23
|
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: 736] [Impact Index Per Article: 122.7] [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.
Collapse
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
| | | |
Collapse
|
|
24
|
Weber F, Junger H, Werner JM, Velez Char N, Rejas C, Schlitt HJ, Hornung M. Increased cytoplasmatic expression of cancer immune surveillance receptor CD1d in anaplastic thyroid carcinomas. Cancer Med 2019; 8:7065-7073. [PMID: 31560833 PMCID: PMC6853836 DOI: 10.1002/cam4.2573] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2019] [Revised: 08/27/2019] [Accepted: 09/10/2019] [Indexed: 12/15/2022] Open
Abstract
BACKGROUND Anaplastic thyroid carcinomas are associated with rapid tumor growth, short survival time and without any promising therapy to improve the poor prognosis. In this study, expression of immunoregulative receptor CD1d and lymphocyte infiltration in different thyroid tumors as well as in healthy tissue were analyzed in order to find new targets for an immunotherapeutic approach. METHODS CD1d immunohistochemistry was performed in samples of 18 anaplastic, 17 follicular, 27 papillary, and 4 medullary thyroid carcinomas as well as in 19 specimens from normal thyroid tissue and additionally in 10 samples of sarcoma, seven malignant melanoma and three spindle-cell lung carcinoma. Furthermore, thyroid samples were stained with antibodies against CD3, CD20, CD56, CD68, and LCA in order to analyze lymphocyte infiltration. RESULTS For the first time CD1d receptor expression on normal thyroid tissue could be demonstrated. Moreover, anaplastic thyroid carcinomas showed significantly higher expression levels compared to other thyroid samples. Most astonishingly, CD1d expression disappeared from the cellular surface and was detected rather in the cytoplasm of anaplastic thyroid carcinoma cells. In addition, histologically similar tumors to anaplastic carcinoma like sarcoma and malignant melanoma revealed distinct CD1d staining patterns. Furthermore, infiltration of T cells, B cells, and macrophages in anaplastic thyroid carcinomas was different when compared to normal thyroid tissue and all other thyroid carcinomas. CONCLUSIONS Anaplastic thyroid carcinomas show significantly higher expression of CD1d, a receptor for NKT cells, which are subject of several anticancer therapy studies. These results may offer a novel approach to explore immunotherapeutic treatment options.
Collapse
Affiliation(s)
- Florian Weber
- Department of Pathology, University Hospital Regensburg, Regensburg, Germany
| | - Henrik Junger
- Department of Surgery, University Hospital Regensburg, Regensburg, Germany
| | - Jens M Werner
- Department of Surgery, University Hospital Regensburg, Regensburg, Germany
| | - Natalia Velez Char
- Department of Pathology, University Hospital Regensburg, Regensburg, Germany
| | - Carolina Rejas
- Department of Surgery, University Hospital Regensburg, Regensburg, Germany
| | - Hans J Schlitt
- Department of Surgery, University Hospital Regensburg, Regensburg, Germany
| | - Matthias Hornung
- Department of Surgery, University Hospital Regensburg, Regensburg, Germany
| |
Collapse
|
|
25
|
Chen D, Gao X, Wang J, Zhao H, Liu H, Chen S, Zhang J, Meng M. Activation of hepatic iNKT2 cells by α-GalCer ameliorates hepatic steatosis induced by high-fat diet in C57BL/6J mice. Int Immunopharmacol 2019; 74:105727. [PMID: 31284229 DOI: 10.1016/j.intimp.2019.105727] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2019] [Revised: 06/25/2019] [Accepted: 06/26/2019] [Indexed: 12/12/2022]
Abstract
The existence of association between the subpopulation of iNKT cells with different functions and nonalcoholic fatty liver disease has not been confirmed. To investigative the role of iNKT cells in the pathogenesis of nonalcoholic fatty liver disease, we established a non-alcoholic fatty liver model by feeding C57BL/6J mice for 12 weeks with a high-fat diet and injecting α-GalCer through different routes to activate hepatic iNKT cells. The liver of the mice fed a high-fat diet (HFD) had severe hepatic steatosis appearance, elevated pro-inflammatory cytokines and reduced anti-inflammatory cytokines in the liver, and high serum levels of TC, LDL, HDL, and ALT. Our results showed that the percentage of iNKT cells in the liver of the HFD-fed mice was lower than that of the control mice. The expression levels of the related transcription factor of T-bet increased but that of GATA-3 decreased in the HFD-fed mice. The administration of α-GalCer by intraperitoneal injection resulted in increasing of hepatic iNKT and iNKT2 cells but decreasing of hepatic iNKT1 cells, and the expression of GATA-3 and anti-inflammatory cytokine (IL-4) was increased in the liver, and hepatic steatosis was ameliorated in the HFD-fed mice. The administration of α-GalCer by subcutaneous injection resulted in a decrease in hepatic iNKT and iNKT2 and an augmentation of hepatic iNKT1 cells. However, hepatic steatosis was not significantly improved. We concluded that the intraperitoneal injection with α-GalCer effectively improved hepatic steatosis, according to increasing the number of hepatic iNKT2 cells. The precise mechanism requires further exploration.
Collapse
Affiliation(s)
- Dongzhi Chen
- Key Laboratory of Pathogenesis Mechanism and Control of Inflammatory-autoimmune Diseases in Hebei Province, Baoding, PR China; Department of Immunology, School of Medicine, Hebei University, Baoding, 071000, Hebei Province, PR China
| | - Xiang Gao
- Key Laboratory of Pathogenesis Mechanism and Control of Inflammatory-autoimmune Diseases in Hebei Province, Baoding, PR China; Department of Immunology, School of Medicine, Hebei University, Baoding, 071000, Hebei Province, PR China
| | - Jianguo Wang
- Affiliated Hospital of Hebei University, Baoding, 071000, Hebei Province, PR China
| | - Huijuan Zhao
- Key Laboratory of Pathogenesis Mechanism and Control of Inflammatory-autoimmune Diseases in Hebei Province, Baoding, PR China; Department of Immunology, School of Medicine, Hebei University, Baoding, 071000, Hebei Province, PR China
| | - Huifang Liu
- Key Laboratory of Pathogenesis Mechanism and Control of Inflammatory-autoimmune Diseases in Hebei Province, Baoding, PR China; Department of Immunology, School of Medicine, Hebei University, Baoding, 071000, Hebei Province, PR China
| | - Shengde Chen
- Key Laboratory of Pathogenesis Mechanism and Control of Inflammatory-autoimmune Diseases in Hebei Province, Baoding, PR China; Department of Immunology, School of Medicine, Hebei University, Baoding, 071000, Hebei Province, PR China
| | - Jingnan Zhang
- Key Laboratory of Pathogenesis Mechanism and Control of Inflammatory-autoimmune Diseases in Hebei Province, Baoding, PR China; Department of Immunology, School of Medicine, Hebei University, Baoding, 071000, Hebei Province, PR China
| | - Ming Meng
- Key Laboratory of Pathogenesis Mechanism and Control of Inflammatory-autoimmune Diseases in Hebei Province, Baoding, PR China; Department of Immunology, School of Medicine, Hebei University, Baoding, 071000, Hebei Province, PR China.
| |
Collapse
|
|
26
|
Biagioli M, Carino A, Fiorucci C, Marchianò S, Di Giorgio C, Roselli R, Magro M, Distrutti E, Bereshchenko O, Scarpelli P, Zampella A, Fiorucci S. GPBAR1 Functions as Gatekeeper for Liver NKT Cells and provides Counterregulatory Signals in Mouse Models of Immune-Mediated Hepatitis. Cell Mol Gastroenterol Hepatol 2019; 8:447-473. [PMID: 31226434 PMCID: PMC6718949 DOI: 10.1016/j.jcmgh.2019.06.003] [Citation(s) in RCA: 41] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/11/2019] [Revised: 06/06/2019] [Accepted: 06/06/2019] [Indexed: 12/18/2022]
Abstract
BACKGROUND & AIMS GPBAR1, also known as TGR5, is a G protein-coupled receptor activated by bile acids. Hepatic innate immune cells are involved in the immunopathogenesis of human liver diseases and in several murine hepatitis models. Here, by using genetic and pharmacological approaches, we provide evidence that GPBAR1 ligation attenuates the inflammation in rodent models of hepatitis. MATERIAL AND METHODS Hepatitis was induced by concanavalin A (Con A) or α-galactosyl-ceramide (α-GalCer). 6b-Ethyl-3a,7b-dihydroxy-5b-cholan-24-ol (BAR501), a selective agonist of GPBAR1, was administrated by o.s. RESULTS In the mouse models of hepatitis, the genetic ablation of Gpabar1 worsened the severity of liver injury and resulted in a type I NKT cells phenotype that was biased toward a NKT1, a proinflammatory, IFN-γ producing, NKT cells subtype. Further on, NKT cells from GPBAR1-/- mice were sufficient to cause a severe hepatitis when transferred to naïve mice. In contrast, GPBAR1 agonism rescued wild-type mice from acute liver damage and redirects the NKT cells polarization toward a NKT10, a regulatory, IL-10 secreting, type I NKT cell subset. In addition, GPBAR1 agonism significantly expanded the subset of IL-10 secreting type II NKT cells. RNAseq analysis of both NKT cells type confirmed that IL-10 is a major target for GPABR1. Accordingly, IL-10 gene ablation abrogated protection afforded by GPBAR1 agonism in the Con A model. CONCLUSION Present results illustrate a role for GPBAR1 in regulating liver NKT ecology. Because NKT cells are an essential component of liver immune system, our data provide a compelling evidence for a GPBAR1-IL-10 axis in regulating of liver immunity.
Collapse
Affiliation(s)
- Michele Biagioli
- Dipartimento di Scienze Biomediche e Chirurgiche, Università di Perugia, Perugia, Italy
| | - Adriana Carino
- Dipartimento di Scienze Biomediche e Chirurgiche, Università di Perugia, Perugia, Italy
| | - Chiara Fiorucci
- Dipartimento di Scienze Biomediche e Chirurgiche, Università di Perugia, Perugia, Italy
| | - Silvia Marchianò
- Dipartimento di Scienze Biomediche e Chirurgiche, Università di Perugia, Perugia, Italy
| | - Cristina Di Giorgio
- Dipartimento di Scienze Biomediche e Chirurgiche, Università di Perugia, Perugia, Italy
| | - Rosalinda Roselli
- Dipartimento di Farmacia, Università di Napoli Federico II, Napoli, Italy
| | - Margherita Magro
- Dipartimento di Scienze Biomediche e Chirurgiche, Università di Perugia, Perugia, Italy
| | - Eleonora Distrutti
- SC di Gastroenterologia ed Epatologia, Azienda Ospedaliera di Perugia, Perugia, Italy
| | - Oxana Bereshchenko
- Dipartimento di Scienze Biomediche e Chirurgiche, Università di Perugia, Perugia, Italy,Department of Medicine, University of Perugia, Perugia, Italy
| | - Paolo Scarpelli
- University of Perugia, Department of Experimental Medicine, Perugia, Italy
| | - Angela Zampella
- Dipartimento di Farmacia, Università di Napoli Federico II, Napoli, Italy
| | - Stefano Fiorucci
- Dipartimento di Scienze Biomediche e Chirurgiche, Università di Perugia, Perugia, Italy,Correspondence Address correspondence to: Stefano Fiorucci, Department of Surgical and Biomedical Science, University of Perugia, Piazza Lucio Severi 1, 06132, S. Andrea delle Fratte, Perugia, Italy. fax: (+39) 075 5858405.
| |
Collapse
|
|
27
|
Characterization of circulating T-, NK-, and NKT cell subsets in patients with colorectal cancer: the peripheral blood immune cell profile. Cancer Immunol Immunother 2019; 68:1011-1024. [PMID: 31053876 PMCID: PMC6529387 DOI: 10.1007/s00262-019-02343-7] [Citation(s) in RCA: 112] [Impact Index Per Article: 18.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2018] [Accepted: 04/16/2019] [Indexed: 12/17/2022]
Abstract
Objective As the development and progression of colorectal cancer (CRC) are known to be affected by the immune system, cell subsets such as T cells, natural killer (NK) cells, and natural killer T (NKT) cells are considered interesting targets for immunotherapy and clinical biomarker research. Until now, the role of systemic immune profiles in tumor progression remains unclear. In this study, we aimed to characterize the immunophenotype of circulating T cells, NK cells, and NKT-like cells in patients with CRC, and to subsequently correlate these immunophenotypes to clinical follow-up data. Methods Using multiparameter flow cytometry, the subset distribution and immunophenotype of T cells (CD3+CD56−), CD56dim NK cells (CD3−CD56dim), CD56bright NK cells (CD3−CD56bright), and NKT-like (CD3+CD56+) cells were investigated in peripheral blood mononuclear cell (PBMC) samples from 71 CRC patients and 19 healthy donors. Results CRC patients showed profound differences in immune cell subset distribution and their immunophenotype compared to healthy donors, as characterized by increased percentage of regulatory T cells, and reduced expression level of the natural cytotoxicity receptors NKp44 and NKp46 on both CD56dim NK cells and NKT-like cells. Finally, we showed in a multivariate analysis that above-median percentage of CD16+ NKT-like cells was independently associated with shorter disease-free survival in CRC patients. Conclusion The altered phenotype of circulating immune cell subsets in CRC and its association with clinical outcome highlight the potential use of PBMC subsets as prognostic biomarkers in CRC, thereby contributing to better insight into the role of systemic immune profiles in tumor progression. Electronic supplementary material The online version of this article (10.1007/s00262-019-02343-7) contains supplementary material, which is available to authorized users.
Collapse
|
|
28
|
Terabe M, Berzofsky JA. Tissue-Specific Roles of NKT Cells in Tumor Immunity. Front Immunol 2018; 9:1838. [PMID: 30158927 PMCID: PMC6104122 DOI: 10.3389/fimmu.2018.01838] [Citation(s) in RCA: 83] [Impact Index Per Article: 11.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2018] [Accepted: 07/25/2018] [Indexed: 01/07/2023] Open
Abstract
NKT cells are an unusual population of T cells recognizing lipids presented by CD1d, a non-classical class-I-like molecule, rather than peptides presented by conventional MHC molecules. Type I NKT cells use a semi-invariant T cell receptor and almost all recognize a common prototype lipid, α-galactosylceramide (α-GalCer). Type II NKT cells are any lipid-specific CD1d-restricted T cells that use other receptors and generally don't recognize α-GalCer. They play important regulatory roles in immunity, including tumor immunity. In contrast to type I NKT cells that most have found to promote antitumor immunity, type II NKT cells suppress tumor immunity and the two subsets cross-regulate each other, forming an immunoregulatory axis. They also can promote other regulatory cells including regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSCs), and can induce MDSCs to secrete TGF-β, one of the most immunosuppressive cytokines known. In some tumors, both Tregs and type II NKT cells can suppress immunosurveillance, and the balance between these is determined by a type I NKT cell. We have also seen that regulation of tumor immunity can depend on the tissue microenvironment, so the same tumor in the same animal in different tissues may be regulated by different cells, such as type II NKT cells in the lung vs Tregs in the skin. Also, the effector T cells that protect those sites when Tregs are removed do not always act between tissues even in the same animal. Thus, metastases may require different immunotherapy from primary tumors. Newly improved sulfatide-CD1d tetramers are starting to allow better characterization of the elusive type II NKT cells to better understand their function and control it to overcome immunosuppression.
Collapse
Affiliation(s)
- Masaki Terabe
- Vaccine Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, United States
| | - Jay A Berzofsky
- Vaccine Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, United States
| |
Collapse
|
|
29
|
Wang H, Hogquist KA. How Lipid-Specific T Cells Become Effectors: The Differentiation of iNKT Subsets. Front Immunol 2018; 9:1450. [PMID: 29997620 PMCID: PMC6028555 DOI: 10.3389/fimmu.2018.01450] [Citation(s) in RCA: 51] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2018] [Accepted: 06/12/2018] [Indexed: 12/24/2022] Open
Abstract
In contrast to peptide-recognizing T cells, invariant natural killer T (iNKT) cells express a semi-invariant T cell receptor that specifically recognizes self- or foreign-lipids presented by CD1d molecules. There are three major functionally distinct effector states for iNKT cells. Owning to these innate-like effector states, iNKT cells have been implicated in early protective immunity against pathogens. Yet, growing evidence suggests that iNKT cells play a role in tissue homeostasis as well. In this review, we discuss current knowledge about the underlying mechanisms that regulate the effector states of iNKT subsets, with a highlight on the roles of a variety of transcription factors and describe how each subset influences different facets of thymus homeostasis.
Collapse
Affiliation(s)
- Haiguang Wang
- Department of Laboratory Medicine and Pathology, Center for Immunology, University of Minnesota, Minneapolis, MN, United States
| | - Kristin A Hogquist
- Department of Laboratory Medicine and Pathology, Center for Immunology, University of Minnesota, Minneapolis, MN, United States
| |
Collapse
|
|
30
|
|
|
31
|
Transcription factor YY1 is essential for iNKT cell development. Cell Mol Immunol 2018; 16:547-556. [PMID: 29500401 DOI: 10.1038/s41423-018-0002-6] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2017] [Revised: 01/09/2018] [Accepted: 01/09/2018] [Indexed: 12/21/2022] Open
Abstract
Invariant natural killer T (iNKT) cells develop from CD4+CD8+ double-positive (DP) thymocytes and express an invariant Vα14-Jα18 T-cell receptor (TCR) α-chain. Generation of these cells requires the prolonged survival of DP thymocytes to allow for Vα14-Jα18 gene rearrangements and strong TCR signaling to induce the expression of the iNKT lineage-specific transcription factor PLZF. Here, we report that the transcription factor Yin Yang 1 (YY1) is essential for iNKT cell formation. Thymocytes lacking YY1 displayed a block in iNKT cell development at the earliest progenitor stage. YY1-deficient thymocytes underwent normal Vα14-Jα18 gene rearrangements, but exhibited impaired cell survival. Deletion of the apoptotic protein BIM failed to rescue the defect in iNKT cell generation. Chromatin immunoprecipitation and deep-sequencing experiments demonstrated that YY1 directly binds and activates the promoter of the Plzf gene. Thus, YY1 plays essential roles in iNKT cell development by coordinately regulating cell survival and PLZF expression.
Collapse
|
|
32
|
Kato S, Berzofsky JA, Terabe M. Possible Therapeutic Application of Targeting Type II Natural Killer T Cell-Mediated Suppression of Tumor Immunity. Front Immunol 2018; 9:314. [PMID: 29520281 PMCID: PMC5827362 DOI: 10.3389/fimmu.2018.00314] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2017] [Accepted: 02/05/2018] [Indexed: 12/17/2022] Open
Abstract
Natural killer T (NKT) cells are a unique T cell subset that exhibits characteristics from both the innate immune cells and T cells. There are at least two subsets of NKT cells, type I and type II. These two subsets of NKT cells have opposite functions in antitumor immunity. Type I NKT cells usually enhance and type II NKT cells suppress antitumor immunity. In addition, these two subsets of NKT cells cross-regulate each other. In this review, we mainly focus on immunosuppressive NKT cells, type II NKT cells. After summarizing their definition, experimental tools to study them, and subsets of them, we will discuss possible therapeutic applications of type II NKT cell pathway targeted therapies.
Collapse
Affiliation(s)
- Shingo Kato
- Department of Gastroenterology and Hepatology, Yokohama City University School of Medicine, Yokohama, Japan
| | - Jay A. Berzofsky
- Molecular Immunogenetics and Vaccine Research Section, Vaccine Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, United States
| | - Masaki Terabe
- Molecular Immunogenetics and Vaccine Research Section, Vaccine Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, United States
| |
Collapse
|
|
33
|
Osman RA, Griebel PJ. CD335 (NKp46) + T-Cell Recruitment to the Bovine Upper Respiratory Tract during a Primary Bovine Herpesvirus-1 Infection. Front Immunol 2017; 8:1393. [PMID: 29114252 PMCID: PMC5660870 DOI: 10.3389/fimmu.2017.01393] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2017] [Accepted: 10/09/2017] [Indexed: 01/30/2023] Open
Abstract
Bovine natural killer (NK) cells were originally defined by the NK activation receptor CD335 [natural killer cell p46-related protein (NKp46)], but following the discovery of NKp46 expression on human T-cells, the definition of conventional bovine NK cells was modified to CD335+CD3− cells. Recently, a bovine T-cell population co-expressing CD335 was identified and these non-conventional T-cells were shown to produce interferon (IFN)-γ and share functional properties with both conventional NK cells and T-cells. It is not known, however, if CD335+ bovine T-cells are recruited to mucosal surfaces and what chemokines play a role in recruiting this unique T-cell subpopulation. In this study, bovine herpesvirus-1 (BHV-1), which is closely related to herpes simplex virus-1, was used to investigate bovine lymphocyte cell populations recruited to the upper respiratory tract following a primary respiratory infection. Immunohistochemical staining with individual monoclonal antibodies revealed significant (P < 0.05) recruitment of CD335+, CD3+, and CD8+ lymphocyte populations to the nasal turbinates on day 5 following primary BHV-1 infection. Dual-color immunofluorescence revealed that cells recruited to nasal turbinates were primarily T-cells that co-expressed both CD335 and CD8. This non-conventional T-cell population represented 77.5% of CD355+ cells and 89.5% of CD8+ cells recruited to nasal turbinates on day 5 post-BHV-1 infection. However, due to diffuse IFN-γ staining of nasal turbinate tissue, it was not possible to directly link increased IFN-γ production following BHV-1 infection with the recruitment of non-conventional T-cells. Transcriptional analysis revealed CCL4, CCL5, and CXCL9 gene expression was significantly (P < 0.05) upregulated in nasal turbinate tissue following BHV-1 infection. Therefore, no single chemokine was associated with recruitment of non-conventional T-cells. In conclusion, the specific recruitment of CD335+ and CD8+ non-conventional T-cells to viral-infected tissue suggests that these cells may play an important role in either the clearance of a primary BHV-1 infection or regulating host responses during viral infection. The early recruitment of non-conventional T-cells following a primary viral infection may enable the host to recognize viral-infected cells through NKp46 while retaining the possibility of establishing T-cell immune memory.
Collapse
Affiliation(s)
- Rahwa A Osman
- Vaccinology and Immunotherapeutics Program, School of Public Health, University of Saskatchewan, Saskatoon, SK, Canada.,Vaccine and Infectious Disease Organization-International Vaccine Centre (VIDO-Intervac), University of Saskatchewan, Saskatoon, SK, Canada
| | - Philip John Griebel
- Vaccinology and Immunotherapeutics Program, School of Public Health, University of Saskatchewan, Saskatoon, SK, Canada.,Vaccine and Infectious Disease Organization-International Vaccine Centre (VIDO-Intervac), University of Saskatchewan, Saskatoon, SK, Canada
| |
Collapse
|
|
34
|
Popovic ZV, Rabionet M, Jennemann R, Krunic D, Sandhoff R, Gröne HJ, Porubsky S. Glucosylceramide Synthase Is Involved in Development of Invariant Natural Killer T Cells. Front Immunol 2017; 8:848. [PMID: 28785267 PMCID: PMC5519558 DOI: 10.3389/fimmu.2017.00848] [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: 02/06/2017] [Accepted: 07/05/2017] [Indexed: 12/11/2022] Open
Abstract
Invariant natural killer T (iNKT) cells represent a unique population of CD1d-restricted T lymphocytes expressing an invariant T cell receptor encoded by Vα14-Jα18 and Vα24-Jα18 gene segments in mice and humans, respectively. Recognition of CD1d-loaded endogenous lipid antigen(s) on CD4/CD8-double positive (DP) thymocytes is essential for the development of iNKT cells. The lipid repertoire of DP thymocytes and the identity of the decisive endogenous lipid ligands have not yet been fully elucidated. Glycosphingolipids (GSL) were implicated to serve as endogenous ligands. However, further in vivo investigations were hampered by early embryonal lethality of mice deficient for the key GSL-synthesizing enzyme glucosylceramide (GlcCer) synthase [GlcCer synthase (GCS), EC 2.4.1.80]. We have now analyzed the GSL composition of DP thymocytes and shown that GlcCer represented the sole neutral GSL and the acidic fraction was composed of gangliosides. Furthermore, we report on a mouse model that by combination of Vav-promoter-driven iCre and floxed GCS alleles (VavCreGCSf/f) enabled an efficient depletion of GCS-derived GSL very early in the T cell development, reaching a reduction by 99.6% in DP thymocytes. Although the general T cell population remained unaffected by this depletion, iNKT cells were reduced by approximately 50% in thymus, spleen, and liver and showed a reduced proliferation and an increased apoptosis rate. The Vβ-chains repertoire and development of iNKT cells remained unaltered. The GSL-depletion neither interfered with expression of CD1d, SLAM, and Ly108 molecules nor impeded the antigen presentation on DP thymocytes. These results indicate that GlcCer-derived GSL, in particular GlcCer, contribute to the homeostatic development of iNKT cells.
Collapse
Affiliation(s)
- Zoran V Popovic
- Cellular and Molecular Pathology, German Cancer Research Center, Heidelberg, Germany.,Institute of Pathology, University Medical Center Mannheim, University of Heidelberg, Mannheim, Germany
| | - Mariona Rabionet
- Cellular and Molecular Pathology, German Cancer Research Center, Heidelberg, Germany
| | - Richard Jennemann
- Cellular and Molecular Pathology, German Cancer Research Center, Heidelberg, Germany
| | - Damir Krunic
- Light Microscopy Facility, German Cancer Research Center, Heidelberg, Germany
| | - Roger Sandhoff
- Cellular and Molecular Pathology, German Cancer Research Center, Heidelberg, Germany
| | - Hermann-Josef Gröne
- Cellular and Molecular Pathology, German Cancer Research Center, Heidelberg, Germany
| | - Stefan Porubsky
- Cellular and Molecular Pathology, German Cancer Research Center, Heidelberg, Germany
| |
Collapse
|
|
35
|
Tsuchiya K, Ikeda T, Batmunkh B, Choijookhuu N, Ishizaki H, Hotokezaka M, Hishikawa Y, Nanashima A. Frequency of CD4+CD161+ T Cell and Interleukin-10 Expression in Inflammatory Bowel Diseases. Acta Histochem Cytochem 2017; 50:21-28. [PMID: 28386147 PMCID: PMC5374100 DOI: 10.1267/ahc.16035] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2016] [Accepted: 12/05/2016] [Indexed: 12/19/2022] Open
Abstract
Mucosal immune dysregulation associated with T cells plays a critical role in the development of inflammatory bowel diseases (IBD). However, the definite significances of these cells in IBD still remain unclear. Therefore, we investigated the population and expression of CD4+CD161+ T cells in the colonic lamina propria mononuclear cells (LPMCs) in patients with IBD by analyses using flow cytometry and immunohistochemistry. Interleukin-10 (IL-10) mRNA levels in both LPMCs and CD4+ T cells in lamina propria (LP-CD4+ T cells) were measured using a real-time quantitative reverse transcription-polymerase chain reaction. IL-10 production was investigated with immunohistochemistry. The results revealed that the population of CD4+CD161+ T cells was significantly decreased in active ulcerative colitis (UC) compared with inactive UC (P < 0.05). The CD4+CD161+ T cell population was inversely correlated with disease activity in patients with UC (r = −0.6326, P = 0.0055), but there was no significant correlation in those with Crohn’s disease. Over-expression of IL-10 mRNA in both LPMCs and LP-CD4+ T cells were detected in active UC. Immunohistochemistry revealed decreased frequency of CD161+ cells and increased IL-10 positive cells in active UC. The frequency of CD4+CD161+ T cells and IL-10 expression was supposed to be associated with the pathological status of mucosal immunoregulation in IBD.
Collapse
Affiliation(s)
- Kazuyo Tsuchiya
- Department of Surgery, Faculty of Medicine, University of Miyazaki
| | - Takuto Ikeda
- Department of Surgery, Faculty of Medicine, University of Miyazaki
| | - Baatarsuren Batmunkh
- Department of Anatomy, Histochemistry and Cell Biology, Faculty of Medicine, University of Miyazaki
| | - Narantsog Choijookhuu
- Department of Anatomy, Histochemistry and Cell Biology, Faculty of Medicine, University of Miyazaki
| | | | | | - Yoshitaka Hishikawa
- Department of Anatomy, Histochemistry and Cell Biology, Faculty of Medicine, University of Miyazaki
| | | |
Collapse
|
|
36
|
Sklarz T, Guan P, Gohil M, Cotton RM, Ge MQ, Haczku A, Das R, Jordan MS. mTORC2 regulates multiple aspects of NKT-cell development and function. Eur J Immunol 2017; 47:516-526. [PMID: 28078715 DOI: 10.1002/eji.201646343] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2016] [Revised: 11/29/2016] [Accepted: 01/10/2017] [Indexed: 11/11/2022]
Abstract
Invariant NKT (iNKT) cells bridge innate and adaptive immunity by rapidly secreting cytokines and lysing targets following TCR recognition of lipid antigens. Based on their ability to secrete IFN-γ, IL-4 and IL-17A, iNKT-cells are classified as NKT-1, NKT-2, and NKT-17 subsets, respectively. The molecular pathways regulating iNKT-cell fate are not fully defined. Recent studies implicate Rictor, a required component of mTORC2, in the development of select iNKT-cell subsets, however these reports are conflicting. To resolve these questions, we used Rictorfl/fl CD4cre+ mice and found that Rictor is required for NKT-17 cell development and normal iNKT-cell cytolytic function. Conversely, Rictor is not absolutely required for IL-4 and IFN-γ production as peripheral iNKT-cells make copious amounts of these cytokines. Overall iNKT-cell numbers are dramatically reduced in the absence of Rictor. We provide data indicating Rictor regulates cell survival as well as proliferation of developing and mature iNKT-cells. Thus, mTORC2 regulates multiple aspects of iNKT-cell development and function.
Collapse
Affiliation(s)
- Tammarah Sklarz
- Abramson Family Cancer Research Center, University of Pennsylvania, Philadelphia, PA, USA
| | - Peng Guan
- Division of Oncology, The Children's Hospital of Philadelphia, Philadelphia, PA, USA
| | - Mercy Gohil
- Abramson Family Cancer Research Center, University of Pennsylvania, Philadelphia, PA, USA
| | - Renee M Cotton
- Abramson Family Cancer Research Center, University of Pennsylvania, Philadelphia, PA, USA
| | - Moyar Q Ge
- Department of Medicine, University of California at Davis, Davis, CA, USA
| | - Angela Haczku
- Department of Medicine, University of California at Davis, Davis, CA, USA
| | - Rupali Das
- Department of Physiology, Michigan State University, East Lansing, MI, USA
| | - Martha S Jordan
- Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| |
Collapse
|
|
37
|
Bianchini E, De Biasi S, Simone AM, Ferraro D, Sola P, Cossarizza A, Pinti M. Invariant natural killer T cells and mucosal-associated invariant T cells in multiple sclerosis. Immunol Lett 2017; 183:1-7. [PMID: 28119072 DOI: 10.1016/j.imlet.2017.01.009] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2017] [Accepted: 01/17/2017] [Indexed: 12/23/2022]
Abstract
Multiple sclerosis (MS) is a chronic progressive inflammatory demyelinating disorder of the central nervous system, and in several countries is a leading cause of permanent neurological disability in young adults, particularly women. MS is considered an autoimmune disease, caused by an aberrant immune response to environmental triggers in genetically susceptible subjects. However, the contribution of the innate or of the adaptive immune system to the development and progression of the disease has not yet been fully elucidated. Innate-like T lymphocytes are unconventional T cells that bridge the innate and adaptive arms of the immune system, because they use a T cell receptor to sense external ligands, but behave like innate cells when they rapidly respond to stimuli. These cells could play an important role in the pathogenesis of MS. Here, we focus on invariant natural killer T (iNKT) cells and mucosal-associated invariant T (MAIT) cells, and we review the current knowledge on their biology and possible involvement in MS. Although several studies have evaluated the frequency and functions of iNKT and MAIT cells both in MS patients and in experimental mouse models, contradictory observations have been reported, and it is not clear whether they exert a protective or a pro-inflammatory and harmful role. A better understanding of how immune cells are involved in MS, and of their interactions could be of great interest for the development of new therapeutic strategies.
Collapse
Affiliation(s)
- Elena Bianchini
- Department of Life Sciences, University of Modena and Reggio Emilia, Via Campi 287, 41125 Modena, Italy
| | - Sara De Biasi
- Department of Surgery, Medicine, Dentistry and Morphological Sciences, University of Modena and Reggio Emilia, Via Campi 287, 41125 Modena, Italy
| | - Anna Maria Simone
- Neurology Unit, Department of Biomedical, Metabolic and Neurosciences, Nuovo Ospedale Civile Sant'Agostino Estense, Via P. Giardini 1355, 41126 Modena, Italy
| | - Diana Ferraro
- Neurology Unit, Department of Biomedical, Metabolic and Neurosciences, Nuovo Ospedale Civile Sant'Agostino Estense, Via P. Giardini 1355, 41126 Modena, Italy
| | - Patrizia Sola
- Neurology Unit, Department of Biomedical, Metabolic and Neurosciences, Nuovo Ospedale Civile Sant'Agostino Estense, Via P. Giardini 1355, 41126 Modena, Italy
| | - Andrea Cossarizza
- Department of Medical and Surgical Sciences of Children and Adults, University of Modena and Reggio Emilia, Via Campi 287, 41125 Modena, Italy.
| | - Marcello Pinti
- Department of Life Sciences, University of Modena and Reggio Emilia, Via Campi 287, 41125 Modena, Italy
| |
Collapse
|
|
38
|
Wu TN, Lin KH, Wu YT, Huang JR, Hung JT, Wu JC, Chen CY, Chu KC, Lin NH, Yu AL, Wong CH. Phenyl Glycolipids with Different Glycosyl Groups Exhibit Marked Differences in Murine and Human iNKT Cell Activation. ACS Chem Biol 2016; 11:3431-3441. [PMID: 27782396 DOI: 10.1021/acschembio.6b00650] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Glycosphingolipids (GSLs) bearing the α-galactosyl headgroup and the acyl chain terminated with a phenyl derivative were found to be more potent than α-galactosyl ceramide (αGalCer) to stimulate both murine and human invariant natural killer T (iNKT) cells and to induce an antibody isotope switch to IgG. In this study, we replaced the galactosyl group with glucose (αGlc) and its fluoro-analogs and found that phenyl GSLs with αGlc (C34-Glc) and its fluoro-analog 6F-C34-Glc were stronger than those with αGal in stimulating human iNKT cells but weaker in mice. Their activities have a strong correlation with the binding avidities of the ternary interaction between the iNKT-cell receptor (iNKTCR) and CD1d-GSL complex. It was the iNKTCR rather than CD1d that dictated the species-specific responses. C34-Glc was further used as an adjuvant for a SSEA4-crm-197 vaccine, and after immunization in mice, the vaccine was highly effective against Lewis lung carcinoma.
Collapse
Affiliation(s)
- Tai-Na Wu
- Genomics
Research Center, Academia Sinica, Taipei, Taiwan
- Institute
of Biochemical Sciences, National Taiwan University, Taipei, Taiwan
| | - Kun-Hsien Lin
- Genomics
Research Center, Academia Sinica, Taipei, Taiwan
- Department
of Chemistry, National Taiwan University, Taipei, Taiwan
| | - Ying-Ta Wu
- Genomics
Research Center, Academia Sinica, Taipei, Taiwan
| | - Jing-Rong Huang
- Institute
of Stem Cell and Translational Cancer Research, Chang Gung Memorial Hospital at Linkou, Taoyuan, Taiwan
| | - Jung-Tung Hung
- Institute
of Stem Cell and Translational Cancer Research, Chang Gung Memorial Hospital at Linkou, Taoyuan, Taiwan
| | - Jen-Chine Wu
- Institute
of Stem Cell and Translational Cancer Research, Chang Gung Memorial Hospital at Linkou, Taoyuan, Taiwan
| | | | | | | | - Alice L. Yu
- Genomics
Research Center, Academia Sinica, Taipei, Taiwan
- Institute
of Stem Cell and Translational Cancer Research, Chang Gung Memorial Hospital at Linkou, Taoyuan, Taiwan
- Chang Gung University, Taoyuan, Taiwan
| | - Chi-Huey Wong
- Genomics
Research Center, Academia Sinica, Taipei, Taiwan
- Institute
of Biochemical Sciences, National Taiwan University, Taipei, Taiwan
- Department
of Chemistry, National Taiwan University, Taipei, Taiwan
- Department
of Chemistry, the Scripps Research Institute, La Jolla, California 92037, United States
| |
Collapse
|
|
39
|
Ando T, Ito H, Ohtaki H, Kanbe A, Hirata A, Hara A, Seishima M. Role of invariant NKT cells in lipopolysaccharide-induced lethal shock during encephalomyocarditis virus infection. Immunobiology 2016; 222:350-357. [PMID: 27665995 DOI: 10.1016/j.imbio.2016.09.005] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2016] [Revised: 08/12/2016] [Accepted: 09/17/2016] [Indexed: 12/19/2022]
Abstract
Viral infections can give rise to secondary bacterial infections. In the present study, we examined the role of invariant natural killer T (iNKT) cells in lipopolysaccharide (LPS)-induced lethal shock during encephalomyocarditis virus (EMCV) infection. Wild-type (WT) mice and Jα18 gene knockout (Jα18 KO) mice were inoculated with EMCV, 5days prior to challenging with LPS. The survival rate of Jα18 KO mice subjected to EMCV and LPS was significantly higher than that of WT mice. TNF-α and nitric oxide (NO) production were increased in WT mice, than that in Jα18 KO mice, after the administration of EMCV and LPS. EMCV infection increased the number of iNKT cells and IFN-γ production by iNKT cells in WT mice. Moreover, EMCV infection enhanced the expression of Toll-like receptor 4 (TLR4) in the lung and spleen. IFN-γ also increased the expression of TLR4 in splenocytes. These findings indicated that EMCV infection activated iNKT cells, and IFN-γ secreted from the iNKT cells up-regulated the expression of TLR4 in various tissues. As a result, EMCV-infected mice were susceptible to LPS and easily developed the lethal shock. In conclusion, iNKT cells were involved in the development of LPS-induced lethal shock during EMCV infection.
Collapse
Affiliation(s)
- Tatsuya Ando
- Department of Informative Clinical Medicine, Gifu University Graduate School of Medicine, 1-1 Yanagido, Gifu 501-1194, Japan
| | - Hiroyasu Ito
- Department of Informative Clinical Medicine, Gifu University Graduate School of Medicine, 1-1 Yanagido, Gifu 501-1194, Japan.
| | - Hirofumi Ohtaki
- Department of Medical Technology, Kansai University of Health Sciences, 2-11-1 Wakaba, Kumatori, Osaka 590-0482, Japan
| | - Ayumu Kanbe
- Department of Informative Clinical Medicine, Gifu University Graduate School of Medicine, 1-1 Yanagido, Gifu 501-1194, Japan
| | - Akihiro Hirata
- Division of Animal Experiment, Life Science Research Center, Gifu University, 1-1 Yanagido, Gifu 501-1194, Japan
| | - Akira Hara
- Department of Tumor Pathology, Gifu University Graduate School of Medicine, 1-1 Yanagido, Gifu 501-1194, Japan
| | - Mitsuru Seishima
- Department of Informative Clinical Medicine, Gifu University Graduate School of Medicine, 1-1 Yanagido, Gifu 501-1194, Japan
| |
Collapse
|
|
40
|
de Vries NL, Swets M, Vahrmeijer AL, Hokland M, Kuppen PJK. The Immunogenicity of Colorectal Cancer in Relation to Tumor Development and Treatment. Int J Mol Sci 2016; 17:ijms17071030. [PMID: 27367680 PMCID: PMC4964406 DOI: 10.3390/ijms17071030] [Citation(s) in RCA: 32] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2016] [Revised: 06/21/2016] [Accepted: 06/23/2016] [Indexed: 02/07/2023] Open
Abstract
Although most cancer types have been viewed as immunologically silent until recently, it has become increasingly clear that the immune system plays key roles in the course of tumor development. Remarkable progress towards understanding cancer immunogenicity and tumor-immune system interactions has revealed important implications for the design of novel immune-based therapies. Natural immune responses, but also therapeutic interventions, can modulate the tumor phenotype due to selective outgrowth of resistant subtypes. This is the result of heterogeneity of tumors, with genetic instability as a driving force, and obviously changes the immunogenicity of tumors. In this review, we discuss the immunogenicity of colorectal cancer (CRC) in relation to tumor development and treatment. As most tumors, CRC activates the immune system in various ways, and is also capable of escaping recognition and elimination by the immune system. Tumor-immune system interactions underlie the balance between immune control and immune escape, and may differ in primary tumors, in the circulation, and in liver metastases of CRC. Since CRC immunogenicity varies between tumors and individuals, novel immune-based therapeutic strategies should not only anticipate the molecular profile, but also the immunological profile of a specific tumor.
Collapse
Affiliation(s)
- Natasja L de Vries
- Department of Surgery, Leiden University Medical Center, Albinusdreef 2, P.O. Box 9600, 2300 RC Leiden, The Netherlands.
- Department of Biomedicine, Aarhus University, Bartholins Allé 6, Build. 1242, DK-8000 Aarhus, Denmark.
| | - Marloes Swets
- Department of Surgery, Leiden University Medical Center, Albinusdreef 2, P.O. Box 9600, 2300 RC Leiden, The Netherlands.
| | - Alexander L Vahrmeijer
- Department of Surgery, Leiden University Medical Center, Albinusdreef 2, P.O. Box 9600, 2300 RC Leiden, The Netherlands.
| | - Marianne Hokland
- Department of Biomedicine, Aarhus University, Bartholins Allé 6, Build. 1242, DK-8000 Aarhus, Denmark.
| | - Peter J K Kuppen
- Department of Surgery, Leiden University Medical Center, Albinusdreef 2, P.O. Box 9600, 2300 RC Leiden, The Netherlands.
| |
Collapse
|
|
41
|
Rydzewski L, Scheffold S, Hecht W, Burkhardt E, Kerner K, Klymiuk MC, Deinzer R, Reinacher M, Henrich M. Identification of a novel feline large granular lymphoma cell line (S87) as non-MHC-restricted cytotoxic T-cell line and assessment of its genetic instability. Vet Immunol Immunopathol 2016; 177:24-34. [PMID: 27436441 DOI: 10.1016/j.vetimm.2016.05.012] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2016] [Revised: 05/01/2016] [Accepted: 05/10/2016] [Indexed: 01/10/2023]
Abstract
Feline large granular lymphocyte lymphomas are rare but very aggressive tumors with a poor prognosis. In this study, a cell line from an abdominal effusion of a cat with large granular lymphoma was characterized. Immunophenotype staining was positive for CD3 and CD45R, and negative for CD4, CD8, CD56, CD79α, BLA.36 and NK1. A TCR γ gene rearrangement was detectable by PARR. Neither FeLV antigen nor exogenous FeLV provirus could be detected. A chromosomal instability associated with a centrosome hyperamplification could also be determined. The cell line is able to lyse target cells without antigen presentation or interaction with antigen presenting cells. Therefore, these cells were classified as genetically instable non-MHC-restricted cytotoxic T cells with large granular lymphocyte morphology.
Collapse
MESH Headings
- Amino Acid Sequence
- Animals
- Base Sequence
- Cat Diseases/genetics
- Cat Diseases/immunology
- Cats/genetics
- Cats/immunology
- Cell Line, Tumor
- Cytotoxicity, Immunologic
- Female
- Gene Rearrangement, gamma-Chain T-Cell Antigen Receptor
- Genes, p53
- Genomic Instability
- Immunophenotyping
- Leukemia Virus, Feline/isolation & purification
- Lymphoma/genetics
- Lymphoma/immunology
- Lymphoma/veterinary
- Microscopy, Electron, Transmission
- RNA, Messenger/genetics
- T-Lymphocytes, Cytotoxic/immunology
- T-Lymphocytes, Cytotoxic/ultrastructure
Collapse
Affiliation(s)
- Lena Rydzewski
- Institute of Veterinary Pathology, Justus-Liebig Universtity Giessen, Frankfurter Strasse 96, 35392 Giessen, Germany.
| | - Svenja Scheffold
- Institute of Veterinary Pathology, Justus-Liebig Universtity Giessen, Frankfurter Strasse 96, 35392 Giessen, Germany
| | - Werner Hecht
- Institute of Veterinary Pathology, Justus-Liebig Universtity Giessen, Frankfurter Strasse 96, 35392 Giessen, Germany
| | - Eberhard Burkhardt
- Institute of Veterinary Pathology, Justus-Liebig Universtity Giessen, Frankfurter Strasse 96, 35392 Giessen, Germany
| | - Katharina Kerner
- Institute of Infectious Disease of Animals, Justus-Liebig University Giessen, Frankfurter Strasse 85-89, 35392 Giessen, Germany
| | - Michele C Klymiuk
- Veterinary Clinic for Obstetrics, Gynecology and Andrology Justus-Liebig Universtity Giessen, Frankfurter Strasse 106, 35392 Giessen,Germany
| | - Renate Deinzer
- Institute for Medical Psychology, Justus-Liebig University Giessen, Friedrichstrasse 36, Giessen, Germany
| | - Manfred Reinacher
- Institute of Veterinary Pathology, Justus-Liebig Universtity Giessen, Frankfurter Strasse 96, 35392 Giessen, Germany
| | - Manfred Henrich
- Institute of Veterinary Pathology, Justus-Liebig Universtity Giessen, Frankfurter Strasse 96, 35392 Giessen, Germany
| |
Collapse
|
|
42
|
Birkholz AM, Howell AR, Kronenberg M. The Alpha and Omega of Galactosylceramides in T Cell Immune Function. J Biol Chem 2015; 290:15365-15370. [PMID: 25947378 DOI: 10.1074/jbc.r115.647057] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022] Open
Abstract
Glycosphingolipids are a subgroup of glycolipids that contain an amino alcohol sphingoid base linked to sugars. They are found in the membranes of cells ranging from bacteria to vertebrates. This group of lipids is known to stimulate the immune system through activation of a type of white blood cell known as natural killer T cell (NKT cell). Here we summarize the extensive research that has been done to identify the structures of natural glycolipids that stimulate NKT cells and to determine how these antigens are recognized. We also review studies designed to understand how glycolipid variants, both natural and synthetic, can alter the responses of NKT cells, leading to dramatic changes in the global immune response.
Collapse
Affiliation(s)
- Alysia M Birkholz
- Division of Developmental Immunology, La Jolla Institute for Allergy and Immunology, La Jolla, California 92037; Division of Biological Sciences, University of California, San Diego, La Jolla, California 92037
| | - Amy R Howell
- Department of Chemistry, University of Connecticut, Storrs, Connecticut 06269
| | - Mitchell Kronenberg
- Division of Developmental Immunology, La Jolla Institute for Allergy and Immunology, La Jolla, California 92037; Division of Biological Sciences, University of California, San Diego, La Jolla, California 92037.
| |
Collapse
|
|
43
|
Miller JFAP, Sadelain M. The journey from discoveries in fundamental immunology to cancer immunotherapy. Cancer Cell 2015; 27:439-49. [PMID: 25858803 DOI: 10.1016/j.ccell.2015.03.007] [Citation(s) in RCA: 172] [Impact Index Per Article: 17.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/27/2015] [Revised: 03/01/2015] [Accepted: 03/16/2015] [Indexed: 01/04/2023]
Abstract
Recent advances in cancer immunotherapy have directly built on 50 years of fundamental and technological advances that made checkpoint blockade and T cell engineering possible. In this review, we intend to show that research, not specifically designed to bring relief or cure to any particular disease, can, when creatively exploited, lead to spectacular results in the management of cancer. The discovery of thymus immune function, T cells, and immune surveillance bore the seeds for today's targeted immune interventions and chimeric antigen receptors.
Collapse
Affiliation(s)
- Jacques F A P Miller
- The Walter and Eliza Hall Institute of Medical Research, Melbourne, VIC 3050, Australia.
| | - Michel Sadelain
- The Center for Cell Engineering, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
| |
Collapse
|
|
44
|
Dossa RG, Alperin DC, Garzon D, Mealey RH, Brown WC, Jervis PJ, Besra GS, Cox LR, Hines SA. In contrast to other species, α-Galactosylceramide (α-GalCer) is not an immunostimulatory NKT cell agonist in horses. DEVELOPMENTAL AND COMPARATIVE IMMUNOLOGY 2015; 49:49-58. [PMID: 25445911 DOI: 10.1016/j.dci.2014.11.005] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/20/2014] [Revised: 11/06/2014] [Accepted: 11/06/2014] [Indexed: 06/04/2023]
Abstract
α-GalCer is a potent immunomodulatory molecule that is presented to NKT cells via the CD1 antigen-presenting system. We hypothesized that when used as an adjuvant α-GalCer would induce protective immune responses against Rhodococcus equi, an important pathogen of young horses. Here we demonstrate that the equine CD1d molecule shares most features found in CD1d from other species and has a suitable lipid-binding groove for presenting glycolipids to NKT cells. However, equine CTL stimulated with α-GalCer failed to kill cells infected with R. equi, and α-GalCer did not increase killing by CTL co-stimulated with R. equi antigen. Likewise, α-GalCer did not induce the lymphoproliferation of equine PBMC or increase the proliferation of R. equi-stimulated cells. Intradermal injection of α-GalCer in horses did not increase the recruitment of lymphocytes or cytokine production. Furthermore, α-GalCer-loaded CD1d tetramers, which have been shown to be broadly cross-reactive, did not bind equine lymphocytes. Altogether, our results demonstrate that in contrast to previously described species, horses are unable to respond to α-GalCer. This raises questions about the capabilities and function of NKT cells and other lipid-specific T lymphocytes in horses.
Collapse
Affiliation(s)
- Robson G Dossa
- Department of Veterinary Microbiology and Pathology, Washington State University, College of Veterinary Medicine, P.O. Box 647040, Pullman, WA 99164-7040, USA
| | - Debra C Alperin
- Department of Veterinary Microbiology and Pathology, Washington State University, College of Veterinary Medicine, P.O. Box 647040, Pullman, WA 99164-7040, USA
| | - Diana Garzon
- Unilever Centre for Molecular Science Informatics, Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, UK
| | - Robert H Mealey
- Department of Veterinary Microbiology and Pathology, Washington State University, College of Veterinary Medicine, P.O. Box 647040, Pullman, WA 99164-7040, USA
| | - Wendy C Brown
- Department of Veterinary Microbiology and Pathology, Washington State University, College of Veterinary Medicine, P.O. Box 647040, Pullman, WA 99164-7040, USA
| | - Peter J Jervis
- School of Biosciences, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK
| | - Gurdyal S Besra
- School of Biosciences, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK
| | - Liam R Cox
- School of Chemistry, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK
| | - Stephen A Hines
- Department of Veterinary Microbiology and Pathology, Washington State University, College of Veterinary Medicine, P.O. Box 647040, Pullman, WA 99164-7040, USA.
| |
Collapse
|
|
45
|
Kang J, Malhotra N. Transcription factor networks directing the development, function, and evolution of innate lymphoid effectors. Annu Rev Immunol 2015; 33:505-38. [PMID: 25650177 PMCID: PMC4674156 DOI: 10.1146/annurev-immunol-032414-112025] [Citation(s) in RCA: 32] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
Mammalian lymphoid immunity is mediated by fast and slow responders to pathogens. Fast innate lymphocytes are active within hours after infections in mucosal tissues. Slow adaptive lymphocytes are conventional T and B cells with clonal antigen receptors that function days after pathogen exposure. A transcription factor (TF) regulatory network guiding early T cell development is at the core of effector function diversification in all innate lymphocytes, and the kinetics of immune responses is set by developmental programming. Operational units within the innate lymphoid system are not classified by the types of pathogen-sensing machineries but rather by discrete effector functions programmed by regulatory TF networks. Based on the evolutionary history of TFs of the regulatory networks, fast effectors likely arose earlier in the evolution of animals to fortify body barriers, and in mammals they often develop in fetal ontogeny prior to the establishment of fully competent adaptive immunity.
Collapse
Affiliation(s)
- Joonsoo Kang
- Department of Pathology, University of Massachusetts Medical School, Worcester, Massachusetts 01655;
| | | |
Collapse
|
|
46
|
NKT cell activation by local α-galactosylceramide administration decreases susceptibility to HSV-2 infection. Immunobiology 2015; 220:762-8. [PMID: 25648689 DOI: 10.1016/j.imbio.2014.12.019] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2014] [Accepted: 12/23/2014] [Indexed: 01/12/2023]
Abstract
NKT cells are a subgroup of T cells, which express a restricted TCR repertoire and are critical for the innate immune responses to viral infections. Activation of NKT cells depends on the major histocompatibility complex-related molecule CD1d, which presents bioactive lipids to NKT cells. The marine sponge derived lipid αGalCer has recently been demonstrated as a specific agonist for activation of human and murine NKT cells. In the present study we investigated the applicability of αGalCer pre-treatment for immune protection against intra-vaginal HSV-2 infection. We found that C57BL/6 WT mice that received local pre-treatment with αGalCer prior to intra-vaginal HSV-2 infection had a lower mean disease score, mortality and viral load in the vagina following infection, compared to mice that did not receive αGalCer pre-treatment. Further, we found increased numbers of CD45 and NK1.1 positive cells in vaginal tissue and elevated levels of IFN-γ in the vaginal tissue and in vaginal fluids 24h after αGalCer pre-treatment. Collectively our data demonstrate a protective effect of αGalCer induced activation of NKT cells in the innate immune protection against viral infection.
Collapse
|
|
47
|
Subrahmanyam PB, Carey GB, Webb TJ. Bcl-xL regulates CD1d-mediated antigen presentation to NKT cells by altering CD1d trafficking through the endocytic pathway. JOURNAL OF IMMUNOLOGY (BALTIMORE, MD. : 1950) 2014; 193:2096-105. [PMID: 25070854 PMCID: PMC4169674 DOI: 10.4049/jimmunol.1400155] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Abstract
NKT cells are a unique subset of T cells that recognize glycolipid Ags presented in the context of CD1d molecules. NKT cells mount strong antitumor responses and are a major focus in developing effective cancer immunotherapy. It is known that CD1d molecules are constantly internalized from the cell surface, recycled through the endocytic compartments, and re-expressed on the cell surface. However, little is known about the regulation of CD1d-mediated Ag processing and presentation in B cell lymphoma. Prosurvival factors of the Bcl-2 family, such as Bcl-xL, are often upregulated in B cell lymphomas and are intimately linked to sphingolipid metabolism, as well as the endocytic compartments. We hypothesized that Bcl-xL can regulate CD1d-mediated Ag presentation to NKT cells. We found that overexpression or induction of Bcl-xL led to increased Ag presentation to NKT cells. Conversely, the inhibition or knockdown of Bcl-xL led to decreased NKT cell activation. Furthermore, knockdown of Bcl-xL resulted in the loss of CD1d trafficking to lysosome-associated membrane protein 1(+) compartments. Rab7, a late endosomal protein, was upregulated and CD1d molecules accumulated in the Rab7(+) late endosomal compartment. These results demonstrate that Bcl-xL regulates CD1d-mediated Ag processing and presentation to NKT cells by altering the late endosomal compartment and changing the intracellular localization of CD1d.
Collapse
Affiliation(s)
- Priyanka B Subrahmanyam
- Department of Microbiology and Immunology, University of Maryland School of Medicine and the Marlene and Stewart Greenebaum Cancer Center, Baltimore, MD 21201
| | - Gregory B Carey
- Department of Microbiology and Immunology, University of Maryland School of Medicine and the Marlene and Stewart Greenebaum Cancer Center, Baltimore, MD 21201
| | - Tonya J Webb
- Department of Microbiology and Immunology, University of Maryland School of Medicine and the Marlene and Stewart Greenebaum Cancer Center, Baltimore, MD 21201
| |
Collapse
|
|
48
|
Paolino M, Choidas A, Wallner S, Pranjic B, Uribesalgo I, Loeser S, Jamieson AM, Langdon WY, Ikeda F, Fededa JP, Cronin SJ, Nitsch R, Schultz-Fademrecht C, Eickhoff J, Menninger S, Unger A, Torka R, Gruber T, Hinterleitner R, Baier G, Wolf D, Ullrich A, Klebl BM, Penninger JM. The E3 ligase Cbl-b and TAM receptors regulate cancer metastasis via natural killer cells. Nature 2014; 507:508-12. [PMID: 24553136 DOI: 10.1038/nature12998] [Citation(s) in RCA: 354] [Impact Index Per Article: 32.2] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2012] [Accepted: 01/03/2014] [Indexed: 12/29/2022]
Abstract
Tumour metastasis is the primary cause of mortality in cancer patients and remains the key challenge for cancer therapy. New therapeutic approaches to block inhibitory pathways of the immune system have renewed hopes for the utility of such therapies. Here we show that genetic deletion of the E3 ubiquitin ligase Cbl-b (casitas B-lineage lymphoma-b) or targeted inactivation of its E3 ligase activity licenses natural killer (NK) cells to spontaneously reject metastatic tumours. The TAM tyrosine kinase receptors Tyro3, Axl and Mer (also known as Mertk) were identified as ubiquitylation substrates for Cbl-b. Treatment of wild-type NK cells with a newly developed small molecule TAM kinase inhibitor conferred therapeutic potential, efficiently enhancing anti-metastatic NK cell activity in vivo. Oral or intraperitoneal administration using this TAM inhibitor markedly reduced murine mammary cancer and melanoma metastases dependent on NK cells. We further report that the anticoagulant warfarin exerts anti-metastatic activity in mice via Cbl-b/TAM receptors in NK cells, providing a molecular explanation for a 50-year-old puzzle in cancer biology. This novel TAM/Cbl-b inhibitory pathway shows that it might be possible to develop a 'pill' that awakens the innate immune system to kill cancer metastases.
Collapse
Affiliation(s)
- Magdalena Paolino
- IMBA, Institute of Molecular Biotechnology of the Austrian Academy of Sciences, 1030 Vienna, Austria
| | - Axel Choidas
- Lead Discovery Center GmbH, D-44227 Dortmund, Germany
| | | | - Blanka Pranjic
- IMBA, Institute of Molecular Biotechnology of the Austrian Academy of Sciences, 1030 Vienna, Austria
| | - Iris Uribesalgo
- IMBA, Institute of Molecular Biotechnology of the Austrian Academy of Sciences, 1030 Vienna, Austria
| | - Stefanie Loeser
- IMBA, Institute of Molecular Biotechnology of the Austrian Academy of Sciences, 1030 Vienna, Austria
| | - Amanda M Jamieson
- Department of Microbiology and Immunology, Brown University, Providence, Rhode Island 02912, USA
| | - Wallace Y Langdon
- School of Pathology and Laboratory Medicine, University of Western Australia, Crawley, Western Australia 6009, Perth, Australia
| | - Fumiyo Ikeda
- IMBA, Institute of Molecular Biotechnology of the Austrian Academy of Sciences, 1030 Vienna, Austria
| | - Juan Pablo Fededa
- IMBA, Institute of Molecular Biotechnology of the Austrian Academy of Sciences, 1030 Vienna, Austria
| | - Shane J Cronin
- IMBA, Institute of Molecular Biotechnology of the Austrian Academy of Sciences, 1030 Vienna, Austria
| | - Roberto Nitsch
- IMBA, Institute of Molecular Biotechnology of the Austrian Academy of Sciences, 1030 Vienna, Austria
| | | | - Jan Eickhoff
- Lead Discovery Center GmbH, D-44227 Dortmund, Germany
| | | | - Anke Unger
- Lead Discovery Center GmbH, D-44227 Dortmund, Germany
| | - Robert Torka
- Max-Planck, Institute for Biochemistry, Department of Molecular Biology, D-82152 Martinsried, Germany
| | - Thomas Gruber
- Medical University Innsbruck, 6020 Innsbruck, Austria
| | | | | | - Dominik Wolf
- 1] Medical University Innsbruck, 6020 Innsbruck, Austria [2] Internal Medicine III, University Hospital Bonn, 53127 Bonn, Germany
| | - Axel Ullrich
- Max-Planck, Institute for Biochemistry, Department of Molecular Biology, D-82152 Martinsried, Germany
| | - Bert M Klebl
- Lead Discovery Center GmbH, D-44227 Dortmund, Germany
| | - Josef M Penninger
- IMBA, Institute of Molecular Biotechnology of the Austrian Academy of Sciences, 1030 Vienna, Austria
| |
Collapse
|
|
49
|
Joshi SK, Lang ML. Fine tuning a well-oiled machine: Influence of NK1.1 and NKG2D on NKT cell development and function. Int Immunopharmacol 2013; 17:260-6. [PMID: 23800654 DOI: 10.1016/j.intimp.2013.05.022] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2013] [Revised: 05/10/2013] [Accepted: 05/24/2013] [Indexed: 01/06/2023]
Abstract
Natural killer T cells (NKT) represent a group of CD1d-restricted T-lineage cells that provide a functional interface between innate and adaptive immune responses in infectious disease, cancer, allergy and autoimmunity. There have been remarkable advances in understanding the molecular events that underpin NKT development in the thymus and in the complex array of functions in the periphery. Most functional studies have focused on activation of T cell antigen receptors expressed by NKT cells and their responses to CD1d presentation of glycolipid and related antigens. Receiving less attention has been several molecules that are hallmarks of Natural Killer (NK) cells, but nonetheless expressed by NKT cells. These include several activating and inhibitory receptors that may fine-tune NKT development and survival, as well as activation via antigen receptors. Herein, we review the possible roles of the NK1.1 and NKG2D receptors in regulating development and function of NKT cells in health and disease. We suggest that pharmacological alteration of NKT activity should consider the potential complexities commensurate with NK1.1 and NKG2D expression.
Collapse
Affiliation(s)
- Sunil K Joshi
- Department of Microbiology and Immunology, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA.
| | | |
Collapse
|
|
50
|
Ghalamfarsa G, Hadinia A, Yousefi M, Jadidi-Niaragh F. The role of natural killer T cells in B cell malignancies. Tumour Biol 2013; 34:1349-60. [DOI: 10.1007/s13277-013-0743-x] [Citation(s) in RCA: 37] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2013] [Accepted: 03/07/2013] [Indexed: 02/08/2023] Open
|