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1
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Chen P, Rehman MU, He Y, Li A, Jian F, Zhang L, Huang S. Exploring the interplay between Eimeria spp. infection and the host: understanding the dynamics of gut barrier function. Vet Q 2025; 45:1-22. [PMID: 39831548 PMCID: PMC11749151 DOI: 10.1080/01652176.2025.2452169] [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: 12/04/2023] [Revised: 07/23/2024] [Accepted: 01/04/2025] [Indexed: 01/22/2025] Open
Abstract
Coccidiosis is a global disease caused by protozoans, typically including Eimeria spp., which pose a significant threat to the normal growth and development of young animals. Coccidiosis affects mainly the gut, where parasite proliferation occurs. The intestinal barrier, which consists of chemical, mechanical, biological, and immune defences, plays a crucial role in protecting the host against pathogens, xenobiotics, and toxins present in the gastrointestinal tract. When animals ingest sporulated Eimeria spp. oocysts, these parasites primarily reproduce in the intestinal tract, causing damage to the structure and function of the intestine. This disruption of intestinal homeostasis adversely affects animal health. Numerous studies have also revealed that Eimeria-infected animals experience slower bone growth rates, inferior meat quality, reduced egg production and quality, as well as impaired growth and development. Therefore, the purpose of this review is to examine the underlying mechanisms through which Eimeria spp. regulate intestinal damage and disturb the balance of the internal environment. Specifically, this review will focus on their effects on the structural basis of the host intestine's chemical, mechanical, biological and immune barriers. This understanding is crucial for the development of effective drugs to prevent the invasion of Eimeria spp. into the intestine, which is of paramount importance for maintaining host health.
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Affiliation(s)
- Pan Chen
- College of Veterinary Medicine, Henan Agricultural University, Zhengzhou, China
| | - Mujeeb Ur Rehman
- Directorate Planning & Development, Livestock & Dairy Development Department Balochistan, Quetta, Pakistan
| | - Yanfeng He
- College of Veterinary Medicine, Henan Agricultural University, Zhengzhou, China
| | - Aoyun Li
- College of Veterinary Medicine, Henan Agricultural University, Zhengzhou, China
| | - Fuchun Jian
- College of Veterinary Medicine, Henan Agricultural University, Zhengzhou, China
| | - Longxian Zhang
- College of Veterinary Medicine, Henan Agricultural University, Zhengzhou, China
| | - Shucheng Huang
- College of Veterinary Medicine, Henan Agricultural University, Zhengzhou, China
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2
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Bai L, Jiang Y, Li X, Yu W, Zhu W, Zhao G, Yang T, Zhou Y, Li J, Li Y. Effects of lipopolysaccharide administration on thymus damage, antioxidant capacity and immune function in weaned piglets. J Vet Res 2025; 69:111-119. [PMID: 40144055 PMCID: PMC11936091 DOI: 10.2478/jvetres-2025-0018] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2024] [Accepted: 03/10/2025] [Indexed: 03/28/2025] Open
Abstract
Introduction Piglets are vulnerable to stress during weaning because of changes in the feeding environment, nutrients, and other growth-impacting conditions. In this study, stress injury was modelled by continuous intraperitoneal injection of lipopolysaccharide (LPS) and was used to investigate the dynamics of antioxidant indices and immunoinflammatory factors in the piglet thymus. Material and Methods Forty-eight weaned piglets were divided into an LPS group and a control group. One group was injected with LPS solution (100 μg/kg) and the other with sterile saline daily. The experiment ran over 13 days, and six piglets from each group were euthanised for necropsy on days 1, 5, 9 and 13. Thymic tissues were collected, and the antioxidant indices and mRNA expression levels of related genes were measured by enzyme activity assay and reverse-transcription quantitative PCR. Results In the LPS group, catalase activities were significantly increased on days 1 and 5, that of superoxide dismutase was significantly higher on day 9 and glutathione activity was elevated throughout. Messenger RNA (mRNA) expression of the toll-like receptor 4 (TLR4) pathway, interleukin (IL) 6, and IL-2 increased in the thymus on day 1. By day 5, the mRNA expression of the TLR pathway, the janus kinase (JAK)/signal transducer and activator of transcription (STAT) pathway, the kelch-like ECH-associated protein 1 (Keap1)/nuclear factor erythroid 2-related factor 2 (Nrf2) pathway, tumour necrosis factor α, IL-10, IL-6 and IL-2 were decreased. On day 13, the mRNA expression levels of the TLR4 and Keap1/Nrf2 pathways, TNF-α, IL-10 and IL-6 increased again. Conclusion Continuous LPS induction led to high activation of the thymic immune system in piglets during the prophase. However, this activation was accompanied by atrophy and immunosuppression mid-experiment. Nevertheless, the immune function gradually recovered in the later stages.
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Affiliation(s)
- Lingna Bai
- College of Animal Science and Technology, Jiangxi Agricultural University, 330045Nanchang, Jiangxi, China
| | - Yijie Jiang
- College of Animal Science and Technology, Jiangxi Agricultural University, 330045Nanchang, Jiangxi, China
| | - Xi Li
- Agricultural Technology Extension Center of Pingxiang City, 337000Pingxiang, Jiangxi, China
| | - Wanting Yu
- College of Animal Science and Technology, Jiangxi Agricultural University, 330045Nanchang, Jiangxi, China
| | - Wenlu Zhu
- College of Animal Science and Technology, Jiangxi Agricultural University, 330045Nanchang, Jiangxi, China
| | - Guotong Zhao
- College of Animal Science and Technology, Jiangxi Agricultural University, 330045Nanchang, Jiangxi, China
| | - Tingyu Yang
- College of Animal Science and Technology, Jiangxi Agricultural University, 330045Nanchang, Jiangxi, China
| | - Yunxiao Zhou
- College of Animal Science and Technology, Jiangxi Agricultural University, 330045Nanchang, Jiangxi, China
| | - Jinyan Li
- College of Animal Science and Technology, Jiangxi Agricultural University, 330045Nanchang, Jiangxi, China
| | - Yong Li
- College of Animal Science and Technology, Jiangxi Agricultural University, 330045Nanchang, Jiangxi, China
- Agricultural Technology Extension Center of Pingxiang City, 337000Pingxiang, Jiangxi, China
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Chen X, Ghanizada M, Mallajosyula V, Sola E, Capasso R, Kathuria KR, Davis MM. Differential roles of human CD4 + and CD8 + regulatory T cells in controlling self-reactive immune responses. Nat Immunol 2025; 26:230-239. [PMID: 39806065 PMCID: PMC11785521 DOI: 10.1038/s41590-024-02062-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2024] [Accepted: 12/10/2024] [Indexed: 01/16/2025]
Abstract
Here we analyzed the relative contributions of CD4+ regulatory T cells expressing Forkhead box protein P3 (FOXP3) and CD8+ regulatory T cells expressing killer cell immunoglobulin-like receptors to the control of autoreactive T and B lymphocytes in human tonsil-derived immune organoids. FOXP3 and GZMB respectively encode proteins FOXP3 and granzyme B, which are critical to the suppressive functions of CD4+ and CD8+ regulatory T cells. Using CRISPR-Cas9 gene editing, we were able to achieve a reduction of ~90-95% in the expression of these genes. FOXP3 knockout in tonsil T cells led to production of antibodies against a variety of autoantigens and increased the affinity of influenza-specific antibodies. By contrast, GZMB knockout resulted in an increase in follicular helper T cells, consistent with the ablation of CD8+ regulatory T cells observed in mouse models, and a marked expansion of autoreactive CD8+ and CD4+ T cells. These findings highlight the distinct yet complementary roles of CD8+ and CD4+ regulatory T cells in regulating cellular and humoral responses to prevent autoimmunity.
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Affiliation(s)
- Xin Chen
- Institute for Immunity, Transplantation, and Infection, Stanford University, Stanford, CA, USA
| | - Mustafa Ghanizada
- Institute for Immunity, Transplantation, and Infection, Stanford University, Stanford, CA, USA
- Department of Immunology and Microbiology, University of Copenhagen, Copenhagen, Denmark
| | - Vamsee Mallajosyula
- Institute for Immunity, Transplantation, and Infection, Stanford University, Stanford, CA, USA
| | - Elsa Sola
- Institute for Immunity, Transplantation, and Infection, Stanford University, Stanford, CA, USA
| | - Robson Capasso
- Division of Sleep Surgery, Department of Otolaryngology-Head and Neck Surgery, Stanford University School of Medicine, Stanford, CA, USA
| | - Karan Raj Kathuria
- Institute for Immunity, Transplantation, and Infection, Stanford University, Stanford, CA, USA
| | - Mark M Davis
- Institute for Immunity, Transplantation, and Infection, Stanford University, Stanford, CA, USA.
- Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, CA, USA.
- The Howard Hughes Medical Institute, Stanford University School of Medicine, Stanford, CA, USA.
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4
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Wrona MV, Ghosh R, Coll K, Chun C, Yousefzadeh MJ. The 3 I's of immunity and aging: immunosenescence, inflammaging, and immune resilience. FRONTIERS IN AGING 2024; 5:1490302. [PMID: 39478807 PMCID: PMC11521913 DOI: 10.3389/fragi.2024.1490302] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 09/02/2024] [Accepted: 09/23/2024] [Indexed: 11/02/2024]
Abstract
As we age, our immune system's ability to effectively respond to pathogens declines, a phenomenon known as immunosenescence. This age-related deterioration affects both innate and adaptive immunity, compromising immune function and leading to chronic inflammation that accelerates aging. Immunosenescence is characterized by alterations in immune cell populations and impaired functionality, resulting in increased susceptibility to infections, diminished vaccine efficacy, and higher prevalence of age-related diseases. Chronic low-grade inflammation further exacerbates these issues, contributing to a decline in overall health and resilience. This review delves into the characteristics of immunosenescence and examines the various intrinsic and extrinsic factors contributing to immune aging and how the hallmarks of aging and cell fates can play a crucial role in this process. Additionally, it discusses the impact of sex, age, social determinants, and gut microbiota health on immune aging, illustrating the complex interplay of these factors in altering immune function. Furthermore, the concept of immune resilience is explored, focusing on the metrics for assessing immune health and identifying strategies to enhance immune function. These strategies include lifestyle interventions such as diet, regular physical activity, stress management, and the use of gerotherapeutics and other approaches. Understanding and mitigating the effects of immunosenescence are crucial for developing interventions that support robust immune responses in aged individuals.
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Affiliation(s)
- Marianna V. Wrona
- Columbia University in the City of New York, New York, NY, United States
| | - Rituparna Ghosh
- Columbia Center for Human Longevity, Columbia University Medical Center, New York, NY, United States
- Columbia Center for Translational Immunology, Columbia University Medical Center, New York, NY, United States
- Department of Medicine, Columbia University Medical Center, New York, NY, United States
| | - Kaitlyn Coll
- Florida International University, Miami, FL, United States
| | - Connor Chun
- Bronx High School of Science, New York, NY, United States
| | - Matthew J. Yousefzadeh
- Columbia University in the City of New York, New York, NY, United States
- Columbia Center for Human Longevity, Columbia University Medical Center, New York, NY, United States
- Columbia Center for Translational Immunology, Columbia University Medical Center, New York, NY, United States
- Department of Medicine, Columbia University Medical Center, New York, NY, United States
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5
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Kattelus R, Starskaia I, Lindén M, Batkulwar K, Pietilä S, Moulder R, Marson A, Rasool O, Suomi T, Elo LL, Lahesmaa R, Buchacher T. Phenotypic profiling of human induced regulatory T cells at early differentiation: insights into distinct immunosuppressive potential. Cell Mol Life Sci 2024; 81:399. [PMID: 39264416 PMCID: PMC11393232 DOI: 10.1007/s00018-024-05429-3] [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: 06/26/2024] [Revised: 08/20/2024] [Accepted: 08/27/2024] [Indexed: 09/13/2024]
Abstract
Regulatory T cells (Tregs) play a key role in suppressing systemic effector immune responses, thereby preventing autoimmune diseases but also potentially contributing to tumor progression. Thus, there is great interest in clinically manipulating Tregs, but the precise mechanisms governing in vitro-induced Treg (iTreg) differentiation are not yet fully understood. Here, we used multiparametric mass cytometry to phenotypically profile human iTregs during the early stages of in vitro differentiation at single-cell level. A panel of 25 metal-conjugated antibodies specific to markers associated with human Tregs was used to characterize these immunomodulatory cells. We found that iTregs highly express the transcription factor FOXP3, as well as characteristic Treg-associated surface markers (e.g. CD25, PD1, CD137, CCR4, CCR7, CXCR3, and CD103). Expression of co-inhibitory factors (e.g. TIM3, LAG3, and TIGIT) increased slightly at late stages of iTreg differentiation. Further, CD103 was upregulated on a subpopulation of iTregs with greater suppressive capacity than their CD103- counterparts. Using mass-spectrometry-based proteomics, we showed that sorted CD103+ iTregs express factors associated with immunosuppression. Overall, our study highlights that during early stages of differentiation, iTregs resemble memory-like Treg features with immunosuppressive activity, and provides opportunities for further investigation into the molecular mechanisms underlying Treg function.
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Affiliation(s)
- Roosa Kattelus
- Turku Bioscience Centre, University of Turku and Åbo Akademi University, Turku, Finland
- InFLAMES Research Flagship Center, University of Turku, Turku, Finland
- Turku Doctoral Programme of Molecular Medicine, University of Turku, Turku, Finland
| | - Inna Starskaia
- Turku Bioscience Centre, University of Turku and Åbo Akademi University, Turku, Finland
- InFLAMES Research Flagship Center, University of Turku, Turku, Finland
- Turku Doctoral Programme of Molecular Medicine, University of Turku, Turku, Finland
| | - Markus Lindén
- Turku Bioscience Centre, University of Turku and Åbo Akademi University, Turku, Finland
- InFLAMES Research Flagship Center, University of Turku, Turku, Finland
| | - Kedar Batkulwar
- Turku Bioscience Centre, University of Turku and Åbo Akademi University, Turku, Finland
- InFLAMES Research Flagship Center, University of Turku, Turku, Finland
| | - Sami Pietilä
- Turku Bioscience Centre, University of Turku and Åbo Akademi University, Turku, Finland
- InFLAMES Research Flagship Center, University of Turku, Turku, Finland
| | - Robert Moulder
- Turku Bioscience Centre, University of Turku and Åbo Akademi University, Turku, Finland
- InFLAMES Research Flagship Center, University of Turku, Turku, Finland
| | - Alexander Marson
- Gladstone-UCSF Institute of Genomic Immunology, San Francisco, CA, 94158, USA
- Department of Medicine, University of California San Francisco, San Francisco, CA, 94143, USA
| | - Omid Rasool
- Turku Bioscience Centre, University of Turku and Åbo Akademi University, Turku, Finland
- InFLAMES Research Flagship Center, University of Turku, Turku, Finland
| | - Tomi Suomi
- Turku Bioscience Centre, University of Turku and Åbo Akademi University, Turku, Finland
- InFLAMES Research Flagship Center, University of Turku, Turku, Finland
- Institute of Biomedicine, University of Turku, Turku, Finland
| | - Laura L Elo
- Turku Bioscience Centre, University of Turku and Åbo Akademi University, Turku, Finland
- InFLAMES Research Flagship Center, University of Turku, Turku, Finland
- Institute of Biomedicine, University of Turku, Turku, Finland
| | - Riitta Lahesmaa
- Turku Bioscience Centre, University of Turku and Åbo Akademi University, Turku, Finland.
- InFLAMES Research Flagship Center, University of Turku, Turku, Finland.
- Institute of Biomedicine, University of Turku, Turku, Finland.
| | - Tanja Buchacher
- Turku Bioscience Centre, University of Turku and Åbo Akademi University, Turku, Finland.
- InFLAMES Research Flagship Center, University of Turku, Turku, Finland.
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6
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Wendering DJ, Amini L, Schlickeiser S, Farrera-Sal M, Schulenberg S, Peter L, Mai M, Vollmer T, Du W, Stein M, Hamm F, Malard A, Castro C, Yang M, Ranka R, Rückert T, Durek P, Heinrich F, Gasparoni G, Salhab A, Walter J, Wagner DL, Mashreghi MF, Landwehr-Kenzel S, Polansky JK, Reinke P, Volk HD, Schmueck-Henneresse M. Effector memory-type regulatory T cells display phenotypic and functional instability. SCIENCE ADVANCES 2024; 10:eadn3470. [PMID: 39231218 PMCID: PMC11421655 DOI: 10.1126/sciadv.adn3470] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/06/2023] [Accepted: 07/30/2024] [Indexed: 09/06/2024]
Abstract
Regulatory T cells (Treg cells) hold promise for sustainable therapy of immune disorders. Recent advancements in chimeric antigen receptor development and genome editing aim to enhance the specificity and function of Treg cells. However, impurities and functional instability pose challenges for the development of safe gene-edited Treg cell products. Here, we examined different Treg cell subsets regarding their fate, epigenomic stability, transcriptomes, T cell receptor repertoires, and function ex vivo and after manufacturing. Each Treg cell subset displayed distinct features, including lineage stability, epigenomics, surface markers, T cell receptor diversity, and transcriptomics. Earlier-differentiated memory Treg cell populations, including a hitherto unidentified naïve-like memory Treg cell subset, outperformed late-differentiated effector memory-like Treg cells in regulatory function, proliferative capacity, and epigenomic stability. High yields of stable, functional Treg cell products could be achieved by depleting the small effector memory-like Treg cell subset before manufacturing. Considering Treg cell subset composition appears critical to maintain lineage stability in the final cell product.
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Affiliation(s)
- Désirée Jacqueline Wendering
- Berlin Institute of Health (BIH) at Charité-Universitätsmedizin Berlin, BIH Center for Regenerative Therapies (BCRT), Development of Biomarkers and Regenerative Therapies, Augustenburger Platz 1, 13353 Berlin, Germany
- Hannover Medical School, Institute of Transfusion Medicine and Transplant Engineering, Carl-Neuberg-Str. 1, 30625 Hannover, Germany
| | - Leila Amini
- Berlin Institute of Health (BIH) at Charité-Universitätsmedizin Berlin, BIH Center for Regenerative Therapies (BCRT), Cell Therapy and Personalized Immunosuppression, Augustenburger Platz 1, 13353 Berlin, Germany
- Berlin Center for Advanced Therapies (BeCAT) at Charité-Universitätsmedizin Berlin, Augustenburger Platz 1, 13353 Berlin, Germany
| | - Stephan Schlickeiser
- Berlin Institute of Health (BIH) at Charité-Universitätsmedizin Berlin, BIH Center for Regenerative Therapies (BCRT), Development of Biomarkers and Regenerative Therapies, Augustenburger Platz 1, 13353 Berlin, Germany
- CheckImmune GmbH, Augustenburger Platz 1, 13353 Berlin, Germany
| | - Martí Farrera-Sal
- Berlin Institute of Health (BIH) at Charité-Universitätsmedizin Berlin, BIH Center for Regenerative Therapies (BCRT), Experimental Immunotherapy, Augustenburger Platz 1, 13353 Berlin, Germany
| | - Sarah Schulenberg
- Berlin Institute of Health (BIH) at Charité-Universitätsmedizin Berlin, BIH Center for Regenerative Therapies (BCRT), Experimental Immunotherapy, Augustenburger Platz 1, 13353 Berlin, Germany
- Einstein Center for Regenerative Therapies at Charité-Universitätsmedizin Berlin, Augustenburger Platz 1, 13353 Berlin, Germany
| | - Lena Peter
- Berlin Institute of Health (BIH) at Charité-Universitätsmedizin Berlin, BIH Center for Regenerative Therapies (BCRT), Experimental Immunotherapy, Augustenburger Platz 1, 13353 Berlin, Germany
- Einstein Center for Regenerative Therapies at Charité-Universitätsmedizin Berlin, Augustenburger Platz 1, 13353 Berlin, Germany
| | - Marco Mai
- Berlin Institute of Health (BIH) at Charité-Universitätsmedizin Berlin, BIH Center for Regenerative Therapies (BCRT), Experimental Immunotherapy, Augustenburger Platz 1, 13353 Berlin, Germany
| | - Tino Vollmer
- Berlin Institute of Health (BIH) at Charité-Universitätsmedizin Berlin, BIH Center for Regenerative Therapies (BCRT), Experimental Immunotherapy, Augustenburger Platz 1, 13353 Berlin, Germany
| | - Weijie Du
- Berlin Center for Advanced Therapies (BeCAT) at Charité-Universitätsmedizin Berlin, Augustenburger Platz 1, 13353 Berlin, Germany
- Berlin Institute of Health (BIH) at Charité-Universitätsmedizin Berlin, BIH Center for Regenerative Therapies (BCRT), Gene Editing for Cell Therapy, Augustenburger Platz 1, 13353 Berlin, Germany
| | - Maik Stein
- Berlin Institute of Health (BIH) at Charité-Universitätsmedizin Berlin, BIH Center for Regenerative Therapies (BCRT), Cell Therapy and Personalized Immunosuppression, Augustenburger Platz 1, 13353 Berlin, Germany
- Berlin Institute of Health (BIH) at Charité-Universitätsmedizin Berlin, BIH Center for Regenerative Therapies (BCRT), Gene Editing for Cell Therapy, Augustenburger Platz 1, 13353 Berlin, Germany
| | - Frederik Hamm
- Berlin Institute of Health (BIH) at Charité-Universitätsmedizin Berlin, BIH Center for Regenerative Therapies (BCRT), Immuno-Epigenetics, Augustenburger Platz 1, 13353 Berlin, Germany
- Deutsches Rheuma-Forschungszentrum Berlin, an Institute of the Leibniz Association, Charitéplatz 1, 10117 Berlin, Germany
| | - Alisier Malard
- Berlin Institute of Health (BIH) at Charité-Universitätsmedizin Berlin, BIH Center for Regenerative Therapies (BCRT), Immuno-Epigenetics, Augustenburger Platz 1, 13353 Berlin, Germany
| | - Carla Castro
- Berlin Institute of Health (BIH) at Charité-Universitätsmedizin Berlin, BIH Center for Regenerative Therapies (BCRT), Immuno-Epigenetics, Augustenburger Platz 1, 13353 Berlin, Germany
| | - Mingxing Yang
- Berlin Institute of Health (BIH) at Charité-Universitätsmedizin Berlin, BIH Center for Regenerative Therapies (BCRT), Immuno-Epigenetics, Augustenburger Platz 1, 13353 Berlin, Germany
| | - Ramon Ranka
- Deutsches Rheuma-Forschungszentrum Berlin, an Institute of the Leibniz Association, Charitéplatz 1, 10117 Berlin, Germany
| | - Timo Rückert
- Deutsches Rheuma-Forschungszentrum Berlin, an Institute of the Leibniz Association, Charitéplatz 1, 10117 Berlin, Germany
| | - Pawel Durek
- Deutsches Rheuma-Forschungszentrum Berlin, an Institute of the Leibniz Association, Charitéplatz 1, 10117 Berlin, Germany
| | - Frederik Heinrich
- Deutsches Rheuma-Forschungszentrum Berlin, an Institute of the Leibniz Association, Charitéplatz 1, 10117 Berlin, Germany
| | - Gilles Gasparoni
- Saarland University, Institute for Genetics/Epigenetics, Saarbrücken, Germany
| | - Abdulrahman Salhab
- Saarland University, Institute for Genetics/Epigenetics, Saarbrücken, Germany
| | - Jörn Walter
- Saarland University, Institute for Genetics/Epigenetics, Saarbrücken, Germany
| | - Dimitrios Laurin Wagner
- Berlin Center for Advanced Therapies (BeCAT) at Charité-Universitätsmedizin Berlin, Augustenburger Platz 1, 13353 Berlin, Germany
- Berlin Institute of Health (BIH) at Charité-Universitätsmedizin Berlin, BIH Center for Regenerative Therapies (BCRT), Gene Editing for Cell Therapy, Augustenburger Platz 1, 13353 Berlin, Germany
- Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Institute of Transfusion Medicine, Charitéplatz 1, 10117 Berlin, Germany
- Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Institute of Medical Immunology, Augustenburger Platz 1, 13353 Berlin, Germany
| | - Mir-Farzin Mashreghi
- Deutsches Rheuma-Forschungszentrum Berlin, an Institute of the Leibniz Association, Charitéplatz 1, 10117 Berlin, Germany
| | - Sybille Landwehr-Kenzel
- Hannover Medical School, Institute of Transfusion Medicine and Transplant Engineering, Carl-Neuberg-Str. 1, 30625 Hannover, Germany
- Berlin Institute of Health (BIH) at Charité-Universitätsmedizin Berlin, BIH Center for Regenerative Therapies (BCRT), Cell Therapy and Personalized Immunosuppression, Augustenburger Platz 1, 13353 Berlin, Germany
- Hannover Medical School, Department of Pediatric Pulmonology, Allergy and Neonatology, Carl-Neuberg-Str. 1, 30625 Hannover, Germany
| | - Julia K Polansky
- Berlin Institute of Health (BIH) at Charité-Universitätsmedizin Berlin, BIH Center for Regenerative Therapies (BCRT), Immuno-Epigenetics, Augustenburger Platz 1, 13353 Berlin, Germany
- Deutsches Rheuma-Forschungszentrum Berlin, an Institute of the Leibniz Association, Charitéplatz 1, 10117 Berlin, Germany
| | - Petra Reinke
- Berlin Institute of Health (BIH) at Charité-Universitätsmedizin Berlin, BIH Center for Regenerative Therapies (BCRT), Cell Therapy and Personalized Immunosuppression, Augustenburger Platz 1, 13353 Berlin, Germany
- Berlin Center for Advanced Therapies (BeCAT) at Charité-Universitätsmedizin Berlin, Augustenburger Platz 1, 13353 Berlin, Germany
| | - Hans-Dieter Volk
- Berlin Institute of Health (BIH) at Charité-Universitätsmedizin Berlin, BIH Center for Regenerative Therapies (BCRT), Development of Biomarkers and Regenerative Therapies, Augustenburger Platz 1, 13353 Berlin, Germany
- Berlin Center for Advanced Therapies (BeCAT) at Charité-Universitätsmedizin Berlin, Augustenburger Platz 1, 13353 Berlin, Germany
- CheckImmune GmbH, Augustenburger Platz 1, 13353 Berlin, Germany
- Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Institute of Medical Immunology, Augustenburger Platz 1, 13353 Berlin, Germany
| | - Michael Schmueck-Henneresse
- Berlin Institute of Health (BIH) at Charité-Universitätsmedizin Berlin, BIH Center for Regenerative Therapies (BCRT), Experimental Immunotherapy, Augustenburger Platz 1, 13353 Berlin, Germany
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7
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Karwig L, Moore PF, Alber G, Eschke M. Distinct characteristics of unique immunoregulatory canine non-conventional TCRαβ pos CD4 negCD8α neg double-negative T cell subpopulations. Front Immunol 2024; 15:1439213. [PMID: 39185407 PMCID: PMC11341405 DOI: 10.3389/fimmu.2024.1439213] [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: 05/27/2024] [Accepted: 07/12/2024] [Indexed: 08/27/2024] Open
Abstract
Conventional CD4pos regulatory T (Treg) cells characterized by expression of the key transcription factor forkhead box P3 (FoxP3) are crucial to control immune responses, thereby maintaining homeostasis and self-tolerance. Within the substantial population of non-conventional T cell receptor (TCR)αβpos CD4negCD8αneg double-negative (dn) T cells of dogs, a novel FoxP3pos Treg-like subset was described that, similar to conventional CD4pos Treg cells, is characterized by high expression of CD25. Noteworthy, human and murine TCRαβpos regulatory dn T cells lack FoxP3. Immunosuppressive capacity of canine dn T cells was hypothesized based on expression of inhibitory molecules (interleukin (IL)-10, cytotoxic T-lymphocyte associated protein 4, CTLA4). Here, to verify their regulatory function, the dnCD25pos (enriched for FoxP3pos Treg-like cells) and the dnCD25neg fraction, were isolated by fluorescence-activated cell sorting from peripheral blood mononuclear cells (PBMC) of Beagle dogs and analyzed in an in vitro suppression assay in comparison to conventional CD4posCD25pos Treg cells (positive control) and CD4posCD25neg T cells (negative control). Canine dnCD25pos T cells suppressed the Concanavalin A-driven proliferation of responder PBMC to a similar extent as conventional CD4posCD25pos Treg cells. Albeit to a lesser extent than FoxP3-enriched dn and CD4posCD25pos populations, even dnCD25neg T cells reduced the proliferation of responder cells. This is remarkable, as dnCD25neg T cells have a FoxP3neg phenotype comparable to non-suppressive CD4posCD25neg T cells. Both, CD25pos and CD25neg dn T cells, can mediate suppression independent of cell-cell contact and do not require additional signals from CD4posCD25neg T cells to secrete inhibitory factors in contrast to CD4posCD25pos T cells. Neutralization of IL-10 completely abrogated the suppression by dnCD25pos and CD4posCD25pos Treg cells in a Transwell™ system, while it only partially reduced suppression by dnCD25neg T cells. Taken together, unique canine non-conventional dnCD25pos FoxP3pos Treg-like cells are potent suppressor cells in vitro. Moreover, inhibition of proliferation of responder T cells by the dnCD25neg fraction indicates suppressive function of a subset of dn T cells even in the absence of FoxP3. The identification of unique immunoregulatory non-conventional dn T cell subpopulations of the dog in vitro is of high relevance, given the immunotherapeutic potential of manipulating regulatory T cell responses in vivo.
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Affiliation(s)
- Laura Karwig
- Institute of Immunology/Molecular Pathogenesis, Center for Biotechnology and Biomedicine, Faculty of Veterinary Medicine, Leipzig University, Leipzig, Germany
| | - Peter F. Moore
- Department of Veterinary Pathology, Microbiology and Immunology, School of Veterinary Medicine, University of California, Davis, Davis, CA, United States
| | - Gottfried Alber
- Institute of Immunology/Molecular Pathogenesis, Center for Biotechnology and Biomedicine, Faculty of Veterinary Medicine, Leipzig University, Leipzig, Germany
| | - Maria Eschke
- Institute of Immunology/Molecular Pathogenesis, Center for Biotechnology and Biomedicine, Faculty of Veterinary Medicine, Leipzig University, Leipzig, Germany
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8
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Ekwe AP, Au R, Zhang P, McEnroe BA, Tan ML, Saldan A, Henden AS, Hutchins CJ, Henderson A, Mudie K, Kerr K, Fuery M, Kennedy GA, Hill GR, Tey SK. Clinical grade multiparametric cell sorting and gene-marking of regulatory T cells. Cytotherapy 2024; 26:719-728. [PMID: 38530690 DOI: 10.1016/j.jcyt.2024.02.023] [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: 07/28/2023] [Revised: 02/25/2024] [Accepted: 02/26/2024] [Indexed: 03/28/2024]
Abstract
BACKGROUND AIMS Regulatory T cells (Tregs) are the main mediators of peripheral tolerance. Treg-directed therapy has shown promising results in preclinical studies of diverse immunopathologies. At present, the clinical applicability of adoptive Treg transfer is limited by difficulties in generating Tregs at sufficient cell dose and purity. METHODS We developed a Good Manufacturing Practice (GMP) compliant method based on closed-system multiparametric Fluorescence-Activated Cell Sorting (FACS) to purify Tregs, which are then expanded in vitro and gene-marked with a clinical grade retroviral vector to enable in vivo fate tracking. Following small-scale optimization, we conducted four clinical-scale processing runs. RESULTS We showed that Tregs could be enriched to 87- 92% purity following FACS-sorting, and expanded and transduced to yield clinically relevant cell dose of 136-732×106 gene-marked cells, sufficient for a cell dose of at least 2 × 106 cells/kg. The expanded Tregs were highly demethylated in the FOXP3 Treg-specific demethylated region (TSDR), consistent with bona fide natural Tregs. They were suppressive in vitro, but a small percentage could secrete proinflammatory cytokines, including interferon-γ and interleukin-17A. CONCLUSIONS This study demonstrated the feasibility of isolating, expanding and gene-marking Tregs in clinical scale, thus paving the way for future phase I trials that will advance knowledge about the in vivo fate of transferred Tregs and its relationship with concomitant Treg-directed pharmacotherapy and clinical response.
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Affiliation(s)
- Adaeze Precious Ekwe
- Translational Cancer Immunotherapy Laboratory, QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia; School of Biomedical Sciences, Faculty of Health, Queensland University of Technology (QUT), Kelvin Grove, Queensland, Australia
| | - Raymond Au
- Translational Cancer Immunotherapy Laboratory, QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia
| | - Ping Zhang
- Translational Cancer Immunotherapy Laboratory, QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia; Translational Science and Therapeutics Division, Fred Hutchinson Cancer Center, Seattle, Washington, USA
| | - Benjamin A McEnroe
- Translational Cancer Immunotherapy Laboratory, QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia
| | - Mei Ling Tan
- Translational Cancer Immunotherapy Laboratory, QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia
| | - Alda Saldan
- Translational Cancer Immunotherapy Laboratory, QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia
| | - Andrea S Henden
- Translational Cancer Immunotherapy Laboratory, QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia; Department of Haematology and Bone Marrow Transplantation, Cancer Care Services, Royal Brisbane and Women's Hospital, Herston, Queensland, Australia; Faculty of Medicine, University of Queensland, St Lucia, Queensland, Australia
| | - Cheryl J Hutchins
- Department of Haematology and Bone Marrow Transplantation, Cancer Care Services, Royal Brisbane and Women's Hospital, Herston, Queensland, Australia
| | - Ashleigh Henderson
- Department of Haematology and Bone Marrow Transplantation, Cancer Care Services, Royal Brisbane and Women's Hospital, Herston, Queensland, Australia
| | - Kari Mudie
- Department of Haematology and Bone Marrow Transplantation, Cancer Care Services, Royal Brisbane and Women's Hospital, Herston, Queensland, Australia
| | - Keri Kerr
- Department of Haematology and Bone Marrow Transplantation, Cancer Care Services, Royal Brisbane and Women's Hospital, Herston, Queensland, Australia
| | - Madonna Fuery
- Department of Haematology and Bone Marrow Transplantation, Cancer Care Services, Royal Brisbane and Women's Hospital, Herston, Queensland, Australia
| | - Glen A Kennedy
- Department of Haematology and Bone Marrow Transplantation, Cancer Care Services, Royal Brisbane and Women's Hospital, Herston, Queensland, Australia; Faculty of Medicine, University of Queensland, St Lucia, Queensland, Australia
| | - Geoffrey R Hill
- Translational Science and Therapeutics Division, Fred Hutchinson Cancer Center, Seattle, Washington, USA
| | - Siok-Keen Tey
- Translational Cancer Immunotherapy Laboratory, QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia; School of Biomedical Sciences, Faculty of Health, Queensland University of Technology (QUT), Kelvin Grove, Queensland, Australia; Department of Haematology and Bone Marrow Transplantation, Cancer Care Services, Royal Brisbane and Women's Hospital, Herston, Queensland, Australia; Faculty of Medicine, University of Queensland, St Lucia, Queensland, Australia.
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9
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Honing DY, Luiten RM, Matos TR. Regulatory T Cell Dysfunction in Autoimmune Diseases. Int J Mol Sci 2024; 25:7171. [PMID: 39000278 PMCID: PMC11241405 DOI: 10.3390/ijms25137171] [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: 06/11/2024] [Accepted: 06/24/2024] [Indexed: 07/16/2024] Open
Abstract
Regulatory T cells (Tregs), a suppressive subpopulation of T cells, are potent mediators of peripheral tolerance, responsible for immune homeostasis. Many autoimmune diseases exhibit disruptions in Treg function or quantity, resulting in an imbalance between protective and pathogenic immune cells. Selective expansion or manipulation of Tregs is a promising therapeutic approach for autoimmune diseases. However, the extensive diversity of Treg subpopulations and the multiple approaches used for Treg identification leads to high complexity, making it difficult to develop a successful treatment capable of modulating Tregs. In this review, we describe the suppressive mechanisms, subpopulations, classification, and identification methodology for Tregs, and their role in the pathogenesis of autoimmune diseases.
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Affiliation(s)
- Dionne Y Honing
- Department of Dermatology, Netherlands Institute for Pigment Disorders, Amsterdam University Medical Centers, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands
- Cancer Center Amsterdam, Amsterdam Institute for Infection and Immunity, 1081 HV Amsterdam, The Netherlands
| | - Rosalie M Luiten
- Department of Dermatology, Netherlands Institute for Pigment Disorders, Amsterdam University Medical Centers, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands
- Cancer Center Amsterdam, Amsterdam Institute for Infection and Immunity, 1081 HV Amsterdam, The Netherlands
| | - Tiago R Matos
- Department of Dermatology, Netherlands Institute for Pigment Disorders, Amsterdam University Medical Centers, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands
- Sanofi, 1105 BP Amsterdam, The Netherlands
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10
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Sheikhlary S, Lopez DH, Moghimi S, Sun B. Recent Findings on Therapeutic Cancer Vaccines: An Updated Review. Biomolecules 2024; 14:503. [PMID: 38672519 PMCID: PMC11048403 DOI: 10.3390/biom14040503] [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: 02/23/2024] [Revised: 04/06/2024] [Accepted: 04/16/2024] [Indexed: 04/28/2024] Open
Abstract
Cancer remains one of the global leading causes of death and various vaccines have been developed over the years against it, including cell-based, nucleic acid-based, and viral-based cancer vaccines. Although many vaccines have been effective in in vivo and clinical studies and some have been FDA-approved, there are major limitations to overcome: (1) developing one universal vaccine for a specific cancer is difficult, as tumors with different antigens are different for different individuals, (2) the tumor antigens may be similar to the body's own antigens, and (3) there is the possibility of cancer recurrence. Therefore, developing personalized cancer vaccines with the ability to distinguish between the tumor and the body's antigens is indispensable. This paper provides a comprehensive review of different types of cancer vaccines and highlights important factors necessary for developing efficient cancer vaccines. Moreover, the application of other technologies in cancer therapy is discussed. Finally, several insights and conclusions are presented, such as the possibility of using cold plasma and cancer stem cells in developing future cancer vaccines, to tackle the major limitations in the cancer vaccine developmental process.
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Affiliation(s)
- Sara Sheikhlary
- Department of Biomedical Engineering, College of Engineering, The University of Arizona, Tucson, AZ 85721, USA
| | - David Humberto Lopez
- Department of Pharmacology and Toxicology, College of Pharmacy, The University of Arizona, Tucson, AZ 85721, USA; (D.H.L.); (S.M.)
| | - Sophia Moghimi
- Department of Pharmacology and Toxicology, College of Pharmacy, The University of Arizona, Tucson, AZ 85721, USA; (D.H.L.); (S.M.)
| | - Bo Sun
- Department of Pharmacology and Toxicology, College of Pharmacy, The University of Arizona, Tucson, AZ 85721, USA; (D.H.L.); (S.M.)
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11
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Stucchi A, Maspes F, Montee-Rodrigues E, Fousteri G. Engineered Treg cells: The heir to the throne of immunotherapy. J Autoimmun 2024; 144:102986. [PMID: 36639301 DOI: 10.1016/j.jaut.2022.102986] [Citation(s) in RCA: 14] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2022] [Accepted: 12/15/2022] [Indexed: 01/13/2023]
Abstract
Recently, increased interest in the use of Tregs as adoptive cell therapy for the treatment of autoimmune diseases and transplant rejection had led to several advances in the field. However, Treg cell therapies, while constantly advancing, indiscriminately suppress the immune system without the permanent stabilization of certain diseases. Genetically modified Tregs hold great promise towards solving these problems, but, challenges in identifying the most potent Treg subtype, accompanied by the ambiguity involved in identifying the optimal Treg source, along with its expansion and engineering in a clinical-grade setting remain paramount. This review highlights the recent advances in methodologies for the development of genetically engineered Treg cell-based treatments for autoimmune, inflammatory diseases, and organ rejection. Additionally, it provides a systematized guide to all the recent progress in the field and informs the readers of the feasibility and safety of engineered adoptive Treg cell therapy, with the aim to provide a framework for researchers involved in the development of engineered Tregs.
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Affiliation(s)
- Adriana Stucchi
- Diabetes Research Institute, IRCCS Ospedale San Raffaele, Milan, Italy
| | - Federica Maspes
- Diabetes Research Institute, IRCCS Ospedale San Raffaele, Milan, Italy
| | - Ely Montee-Rodrigues
- Diabetes Research Institute, IRCCS Ospedale San Raffaele, Milan, Italy; Cambridge Epigenetix, Cambridge, Cambridgeshire, United Kingdom
| | - Georgia Fousteri
- Diabetes Research Institute, IRCCS Ospedale San Raffaele, Milan, Italy.
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12
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Ouyang P, Wang L, Wu J, Tian Y, Chen C, Li D, Yao Z, Chen R, Xiang G, Gong J, Bao Z. Overcoming cold tumors: a combination strategy of immune checkpoint inhibitors. Front Immunol 2024; 15:1344272. [PMID: 38545114 PMCID: PMC10965539 DOI: 10.3389/fimmu.2024.1344272] [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: 11/25/2023] [Accepted: 02/26/2024] [Indexed: 04/12/2024] Open
Abstract
Immune Checkpoint Inhibitors (ICIs) therapy has advanced significantly in treating malignant tumors, though most 'cold' tumors show no response. This resistance mainly arises from the varied immune evasion mechanisms. Hence, understanding the transformation from 'cold' to 'hot' tumors is essential in developing effective cancer treatments. Furthermore, tumor immune profiling is critical, requiring a range of diagnostic techniques and biomarkers for evaluation. The success of immunotherapy relies on T cells' ability to recognize and eliminate tumor cells. In 'cold' tumors, the absence of T cell infiltration leads to the ineffectiveness of ICI therapy. Addressing these challenges, especially the impairment in T cell activation and homing, is crucial to enhance ICI therapy's efficacy. Concurrently, strategies to convert 'cold' tumors into 'hot' ones, including boosting T cell infiltration and adoptive therapies such as T cell-recruiting bispecific antibodies and Chimeric Antigen Receptor (CAR) T cells, are under extensive exploration. Thus, identifying key factors that impact tumor T cell infiltration is vital for creating effective treatments targeting 'cold' tumors.
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Affiliation(s)
- Peng Ouyang
- Department of General Surgery, The First Affiliated Hospital of Jinan University, Guangzhou, Guangdong, China
| | - Lijuan Wang
- Department of Pathophysiology, School of Medicine, Jinan University, Guangzhou, Guangdong, China
| | - Jianlong Wu
- Department of General Surgery, The First Affiliated Hospital of Jinan University, Guangzhou, Guangdong, China
| | - Yao Tian
- Department of General Surgery, The First Affiliated Hospital of Jinan University, Guangzhou, Guangdong, China
| | - Caiyun Chen
- Department of General Surgery, The First Affiliated Hospital of Jinan University, Guangzhou, Guangdong, China
| | - Dengsheng Li
- Department of General Surgery, The First Affiliated Hospital of Jinan University, Guangzhou, Guangdong, China
| | - Zengxi Yao
- Department of General Surgery, The First Affiliated Hospital of Jinan University, Guangzhou, Guangdong, China
| | - Ruichang Chen
- Department of General Surgery, The First Affiliated Hospital of Jinan University, Guangzhou, Guangdong, China
| | - Guoan Xiang
- Department of General Surgery, Guangdong Second Provincial General Hospital, Guangzhou, Guangdong, China
| | - Jin Gong
- Department of General Surgery, The First Affiliated Hospital of Jinan University, Guangzhou, Guangdong, China
| | - Zhen Bao
- Department of General Surgery, The First Affiliated Hospital of Jinan University, Guangzhou, Guangdong, China
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13
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Mattisson J, Halvardson J, Davies H, Bruhn-Olszewska B, Olszewski P, Danielsson M, Bjurling J, Lindberg A, Zaghlool A, Rychlicka-Buniowska E, Dumanski JP, Forsberg LA. Loss of chromosome Y in regulatory T cells. BMC Genomics 2024; 25:243. [PMID: 38443832 PMCID: PMC10913415 DOI: 10.1186/s12864-024-10168-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2023] [Accepted: 02/28/2024] [Indexed: 03/07/2024] Open
Abstract
BACKGROUND Mosaic loss of chromosome Y (LOY) in leukocytes is the most prevalent somatic aneuploidy in aging humans. Men with LOY have increased risks of all-cause mortality and the major causes of death, including many forms of cancer. It has been suggested that the association between LOY and disease risk depends on what type of leukocyte is affected with Y loss, with prostate cancer patients showing higher levels of LOY in CD4 + T lymphocytes. In previous studies, Y loss has however been observed at relatively low levels in this cell type. This motivated us to investigate whether specific subsets of CD4 + T lymphocytes are particularly affected by LOY. Publicly available, T lymphocyte enriched, single-cell RNA sequencing datasets from patients with liver, lung or colorectal cancer were used to study how LOY affects different subtypes of T lymphocyte. To validate the observations from the public data, we also generated a single-cell RNA sequencing dataset comprised of 23 PBMC samples and 32 CD4 + T lymphocytes enriched samples. RESULTS Regulatory T cells had significantly more LOY than any other studied T lymphocytes subtype. Furthermore, LOY in regulatory T cells increased the ratio of regulatory T cells compared with other T lymphocyte subtypes, indicating an effect of Y loss on lymphocyte differentiation. This was supported by developmental trajectory analysis of CD4 + T lymphocytes culminating in the regulatory T cells cluster most heavily affected by LOY. Finally, we identify dysregulation of 465 genes in regulatory T cells with Y loss, many involved in the immunosuppressive functions and development of regulatory T cells. CONCLUSIONS Here, we show that regulatory T cells are particularly affected by Y loss, resulting in an increased fraction of regulatory T cells and dysregulated immune functions. Considering that regulatory T cells plays a critical role in the process of immunosuppression; this enrichment for regulatory T cells with LOY might contribute to the increased risk for cancer observed among men with Y loss in leukocytes.
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Affiliation(s)
- Jonas Mattisson
- Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, Uppsala, Sweden
| | - Jonatan Halvardson
- Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, Uppsala, Sweden
| | - Hanna Davies
- Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, Uppsala, Sweden
| | - Bożena Bruhn-Olszewska
- Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, Uppsala, Sweden
| | - Paweł Olszewski
- 3P-Medicine Laboratory, Medical University of Gdańsk, Gdańsk, Poland
| | - Marcus Danielsson
- Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, Uppsala, Sweden
| | - Josefin Bjurling
- Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, Uppsala, Sweden
| | - Amanda Lindberg
- Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, Uppsala, Sweden
| | - Ammar Zaghlool
- Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, Uppsala, Sweden
| | | | - Jan P Dumanski
- Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, Uppsala, Sweden
- 3P-Medicine Laboratory, Medical University of Gdańsk, Gdańsk, Poland
| | - Lars A Forsberg
- Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, Uppsala, Sweden
- The Beijer Laboratory, Uppsala University, Uppsala, Sweden
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14
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Song D, Ding Y. A new target of radiotherapy combined with immunotherapy: regulatory T cells. Front Immunol 2024; 14:1330099. [PMID: 38259489 PMCID: PMC10800811 DOI: 10.3389/fimmu.2023.1330099] [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: 10/30/2023] [Accepted: 12/11/2023] [Indexed: 01/24/2024] Open
Abstract
Radiotherapy is one important treatment for malignant tumours. It is widely believed today that radiotherapy has not only been used as a local tumour treatment method, but also can induce systemic anti-tumour responses by influencing the tumour microenvironment, but its efficacy is limited by the tumour immunosuppression microenvironment. With the advancement of technology, immunotherapy has entered a golden age of rapid development, gradually occupying a place in clinical tumour treatment. Regulatory T cells (Tregs) widely distributing in the tumour microenvironment play an important role in mediating tumour development. This article analyzes immunotherapy, the interaction between Tregs, tumours and radiotherapy. It briefly introduces immunotherapies targeting Tregs, aiming to provide new strategies for radiotherapy combined with Immunotherapy.
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Affiliation(s)
| | - Yun Ding
- Department of Radiation Oncology, The Third Affiliated Hospital of Soochow University, Changzhou, China
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15
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Baron KJ, Turnquist HR. Clinical Manufacturing of Regulatory T Cell Products For Adoptive Cell Therapy and Strategies to Improve Therapeutic Efficacy. Organogenesis 2023; 19:2164159. [PMID: 36681905 PMCID: PMC9870008 DOI: 10.1080/15476278.2022.2164159] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/23/2023] Open
Abstract
Based on successes in preclinical animal transplant models, adoptive cell therapy (ACT) with regulatory T cells (Tregs) is a promising modality to induce allograft tolerance or reduce the use of immunosuppressive drugs to prevent rejection. Extensive work has been done in optimizing the best approach to manufacture Treg cell products for testing in transplant recipients. Collectively, clinical evaluations have demonstrated that large numbers of Tregs can be expanded ex vivo and infused safely. However, these trials have failed to induce robust drug-free tolerance and/or significantly reduce the level of immunosuppression needed to prevent solid organ transplant (SOTx) rejection. Improving Treg therapy effectiveness may require increasing Treg persistence or orchestrating Treg migration to secondary lymphatic tissues or places of inflammation. In this review, we describe current clinical Treg manufacturing methods used for clinical trials. We also highlight current strategies being implemented to improve delivered Treg ACT persistence and migration in preclinical studies.
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Affiliation(s)
- Kassandra J. Baron
- Departments of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA,Thomas E. Starzl Transplantation Institute, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA,Department of Infectious Disease and Microbiology, University of Pittsburgh School of Public Health, Pittsburgh, Pennsylvania, USA
| | - Hēth R. Turnquist
- Departments of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA,Thomas E. Starzl Transplantation Institute, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA,Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA,McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA,CONTACT Hēth R. Turnquist Departments of Surgery, University of Pittsburgh School of Medicine, Thomas E. Starzl Transplantation Institute 200 Lothrop Street, BST W1542, PittsburghPA 15213, USA
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16
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El-Sayed MM, Mohak S, Gala D, Fabian R, Peterfi Z, Fabian Z. The Role of the Intestinal Microbiome in Multiple Sclerosis-Lessons to Be Learned from Hippocrates. BIOLOGY 2023; 12:1463. [PMID: 38132289 PMCID: PMC10740531 DOI: 10.3390/biology12121463] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/25/2023] [Revised: 11/16/2023] [Accepted: 11/18/2023] [Indexed: 12/23/2023]
Abstract
Based on recent advances in research of chronic inflammatory conditions, there is a growing body of evidence that suggests a close correlation between the microbiota of the gastrointestinal tract and the physiologic activity of the immune system. This raises the idea that disturbances of the GI ecosystem contribute to the unfolding of chronic diseases including neurodegenerative pathologies. Here, we overview our current understanding on the putative interaction between the gut microbiota and the immune system from the aspect of multiple sclerosis, one of the autoimmune conditions accompanied by severe chronic neuroinflammation that affects millions of people worldwide.
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Affiliation(s)
- Mohamed Mahmoud El-Sayed
- School of Medicine and Dentistry, Faculty of Clinical and Biomedical Sciences, University of Central Lancashire, Fylde Rd, Preston PR1 2HE, UK;
| | - Sidhesh Mohak
- Department of Clinical Sciences, Saint James School of Medicine, Park Ridge, IL 60068, USA;
| | - Dhir Gala
- American University of the Caribbean School of Medicine, 1 University Drive, Jordan Road, Cupecoy, St Marteen, The Netherlands;
| | - Reka Fabian
- Salerno, Secondary School, Threadneedle Road, H91 D9H3 Galway, Ireland;
| | - Zoltan Peterfi
- Division of Infectology, 1st Department of Internal Medicine, University of Pecs, Clinical Centre, 7623 Pécs, Hungary;
| | - Zsolt Fabian
- School of Medicine and Dentistry, Faculty of Clinical and Biomedical Sciences, University of Central Lancashire, Fylde Rd, Preston PR1 2HE, UK;
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17
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Churov AV, Chegodaev YS, Khotina VA, Ofitserov VP, Orekhov AN. Regulatory T Cells in Atherosclerosis: Is Adoptive Cell Therapy Possible? Life (Basel) 2023; 13:1931. [PMID: 37763334 PMCID: PMC10532736 DOI: 10.3390/life13091931] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2023] [Revised: 08/08/2023] [Accepted: 08/18/2023] [Indexed: 09/29/2023] Open
Abstract
Atherosclerosis is an insidious vascular disease with an asymptomatic debut and development over decades. The aetiology and pathogenesis of atherosclerosis are not completely clear. However, chronic inflammation and autoimmune reactions play a significant role in the natural course of atherosclerosis. The pathogenesis of atherosclerosis involves damage to the intima, immune cell recruitment and infiltration of cells such as monocytes/macrophages, neutrophils, and lymphocytes into the inner layer of vessel walls, and the accumulation of lipids, leading to vascular inflammation. The recruited immune cells mainly have a pro-atherogenic effect, whereas CD4+ regulatory T (Treg) cells are another heterogeneous group of cells with opposite functions that suppress the pathogenic immune responses. Present in low numbers in atherosclerotic plaques, Tregs serve a protective role, maintaining immune homeostasis and tolerance by suppressing pro-inflammatory immune cell subsets. Compelling experimental data suggest that various Treg cell-based approaches may be important in the treatment of atherosclerosis. Here we highlight the most recent advances in our understanding of the roles of FOXP3-expressing CD4+ Treg cells in the atherogenic process and discuss potential translational strategies for the treatment of atherosclerosis by Treg manipulation.
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Affiliation(s)
- Alexey V. Churov
- Institute on Aging Research, Russian Gerontology Clinical Research Center, Pirogov Russian National Research Medical University, 129226 Moscow, Russia
| | - Yegor S. Chegodaev
- Institute of General Pathology and Pathophysiology, 8 Baltiiskaya Street, 125315 Moscow, Russia
| | - Victoria A. Khotina
- Institute of General Pathology and Pathophysiology, 8 Baltiiskaya Street, 125315 Moscow, Russia
| | - Vladimir P. Ofitserov
- Moscow Aviation Institute, National Research University, 4 Volokolamskoe Shosse, 125993 Moscow, Russia
| | - Alexander N. Orekhov
- Institute of General Pathology and Pathophysiology, 8 Baltiiskaya Street, 125315 Moscow, Russia
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Buxbaum NP, Socié G, Hill GR, MacDonald KPA, Tkachev V, Teshima T, Lee SJ, Ritz J, Sarantopoulos S, Luznik L, Zeng D, Paczesny S, Martin PJ, Pavletic SZ, Schultz KR, Blazar BR. Chronic GvHD NIH Consensus Project Biology Task Force: evolving path to personalized treatment of chronic GvHD. Blood Adv 2023; 7:4886-4902. [PMID: 36322878 PMCID: PMC10463203 DOI: 10.1182/bloodadvances.2022007611] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2022] [Revised: 10/26/2022] [Accepted: 10/26/2022] [Indexed: 01/26/2023] Open
Abstract
Chronic graft-versus-host disease (cGvHD) remains a prominent barrier to allogeneic hematopoietic stem cell transplantion as the leading cause of nonrelapse mortality and significant morbidity. Tremendous progress has been achieved in both the understanding of pathophysiology and the development of new therapies for cGvHD. Although our field has historically approached treatment from an empiric position, research performed at the bedside and bench has elucidated some of the complex pathophysiology of cGvHD. From the clinical perspective, there is significant variability of disease manifestations between individual patients, pointing to diverse biological underpinnings. Capitalizing on progress made to date, the field is now focused on establishing personalized approaches to treatment. The intent of this article is to concisely review recent knowledge gained and formulate a path toward patient-specific cGvHD therapy.
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Affiliation(s)
- Nataliya P. Buxbaum
- Department of Pediatrics, Roswell Park Comprehensive Cancer Center, Buffalo, NY
| | - Gerard Socié
- Hematology-Transplantation, Assistance Publique-Hopitaux de Paris & University of Paris – INSERM UMR 676, Hospital Saint Louis, Paris, France
| | - Geoffrey R. Hill
- Division of Medical Oncology, The University of Washington, Seattle, WA
- Division of Clinical Research, Fred Hutchinson Cancer Research Center, Seattle, WA
| | - Kelli P. A. MacDonald
- Department of Immunology, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia
| | - Victor Tkachev
- Division of Hematology/Oncology, Boston Children's Hospital, Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA
- Department of Pediatrics, Harvard Medical School, Boston, MA
| | - Takanori Teshima
- Department of Hematology, Hokkaido University Faculty of Medicine, Sapporo, Japan
| | - Stephanie J. Lee
- Division of Clinical Research, Fred Hutchinson Cancer Research Center, Seattle, WA
| | - Jerome Ritz
- Dana-Farber Cancer Institute, Harvard Medical School, Brigham and Women’s Hospital, Boston, MA
| | - Stefanie Sarantopoulos
- Department of Medicine, Division of Hematologic Malignancies and Cellular Therapy, Duke University Medical Center, Duke Cancer Institute, Durham, NC
| | - Leo Luznik
- Division of Hematologic Malignancies, Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD
| | - Defu Zeng
- Arthur D. Riggs Diabetes and Metabolism Research Institute, The Beckman Research Institute, Hematologic Maligancies and Stem Cell Transplantation Institute, City of Hope National Medical Center, Duarte, CA
| | - Sophie Paczesny
- Department of Microbiology and Immunology and Cancer Immunology Program, Hollings Cancer Center, Medical University of South Carolina, Charleston, SC
| | - Paul J. Martin
- Division of Clinical Research, Fred Hutchinson Cancer Research Center, Seattle, WA
| | - Steven Z. Pavletic
- Immune Deficiency Cellular Therapy Program, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD
| | - Kirk R. Schultz
- Michael Cuccione Childhood Cancer Research Program, British Columbia Children’s Hospital, University of British Columbia, Vancouver, BC, Canada
| | - Bruce R. Blazar
- Department of Pediatrics, Division of Blood & Marrow Transplant & Cellular Therapy, University of Minnesota, Minneappolis, MN
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19
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Hu Y, Li Z, Zhang Y, Wu Y, Liu Z, Zeng J, Hao Z, Li J, Ren J, Yao M. The Evolution of Tumor Microenvironment in Gliomas and Its Implication for Target Therapy. Int J Biol Sci 2023; 19:4311-4326. [PMID: 37705736 PMCID: PMC10496508 DOI: 10.7150/ijbs.83531] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2023] [Accepted: 08/03/2023] [Indexed: 09/15/2023] Open
Abstract
Gliomas develop in unique and complicated environments that nourish tumor cells. The tumor microenvironment (TME) of gliomas comprises heterogeneous cells, including brain-resident cells, immune cells, and vascular cells. Reciprocal interactions among these cells are involved in the evolution of the TME. Moreover, the study of attractive therapeutic strategies that target the TME is transitioning from basic research to the clinic. Mouse models are indispensable tools for dissecting the processes and mechanisms leading to TME evolution. In this review, we overview the paradoxical roles of the TME, as well as the recent progress of mouse models in TME research. Finally, we summarize recent advances in TME-targeting therapeutic strategies.
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Affiliation(s)
- Yang Hu
- The First Affiliated Hospital of Guangzhou Medical University, Guangzhou Institute of Respiratory Disease & China State Key Laboratory of Respiratory Disease, Guangzhou, 510182, China
| | - Zhixing Li
- The First Affiliated Hospital of Guangzhou Medical University, Guangzhou Institute of Respiratory Disease & China State Key Laboratory of Respiratory Disease, Guangzhou, 510182, China
| | - Yichi Zhang
- The First Affiliated Hospital of Guangzhou Medical University, Guangzhou Institute of Respiratory Disease & China State Key Laboratory of Respiratory Disease, Guangzhou, 510182, China
| | - Yuzheng Wu
- The First Affiliated Hospital of Guangzhou Medical University, Guangzhou Institute of Respiratory Disease & China State Key Laboratory of Respiratory Disease, Guangzhou, 510182, China
| | - Zihao Liu
- The First Affiliated Hospital of Guangzhou Medical University, Guangzhou Institute of Respiratory Disease & China State Key Laboratory of Respiratory Disease, Guangzhou, 510182, China
| | - Jianhao Zeng
- Department of Microbiology, Immunology, and Cancer Biology, University of Virginia Health System, Charlottesville, VA 22908, USA
| | - Zhexue Hao
- The First Affiliated Hospital of Guangzhou Medical University, Guangzhou Institute of Respiratory Disease & China State Key Laboratory of Respiratory Disease, Guangzhou, 510182, China
| | - Jin Li
- The First Affiliated Hospital of Guangzhou Medical University, Guangzhou Institute of Respiratory Disease & China State Key Laboratory of Respiratory Disease, Guangzhou, 510182, China
| | - Jiaoyan Ren
- School of Food Sciences and Engineering, South China University of Technology, Guangzhou, 510641, China
| | - Maojin Yao
- The First Affiliated Hospital of Guangzhou Medical University, Guangzhou Institute of Respiratory Disease & China State Key Laboratory of Respiratory Disease, Guangzhou, 510182, China
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20
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Harris F, Berdugo YA, Tree T. IL-2-based approaches to Treg enhancement. Clin Exp Immunol 2023; 211:149-163. [PMID: 36399073 PMCID: PMC10019135 DOI: 10.1093/cei/uxac105] [Citation(s) in RCA: 35] [Impact Index Per Article: 17.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2022] [Revised: 09/12/2022] [Accepted: 11/17/2022] [Indexed: 11/19/2022] Open
Abstract
Immune homeostasis is heavily dependent on the action of regulatory T cells (Tregs) which act to suppress the activation of many immune cell types including autoreactive conventional T cells. A body of evidence has shown that Tregs are intrinsically defective in many common autoimmune diseases, and gene polymorphisms which increase the susceptibility of autoimmune disease development have implicated the interleukin-2 (IL-2) signaling pathway as a key dysregulated mechanism. IL-2 is essential for Treg function and survival, and Tregs are highly sensitive to low levels of this cytokine in their environment. This review will revisit the rationale behind using low-dose IL-2 as a therapy to treat autoimmune diseases and evaluate the outcomes of trials to date. Furthermore, novel engineered IL-2 therapies with increased Treg specificity have shown promise in pre-clinical studies and human clinical trials for some agents have begun. Future studies will determine whether low-dose IL-2 or engineered IL-2 therapies can change the course of autoimmune and inflammatory diseases in patients.
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Affiliation(s)
- Ffion Harris
- Department of Immunobiology, Faculty of Life Sciences and Medicine, King’s College, London, UK
| | - Yoana Arroyo Berdugo
- Department of Immunobiology, Faculty of Life Sciences and Medicine, King’s College, London, UK
| | - Timothy Tree
- Department of Immunobiology, Faculty of Life Sciences and Medicine, King’s College, London, UK
- National Institute of Health Research Biomedical Research Centre at Guy’s and St. Thomas’ National Health Service Foundation Trust, King’s College London, London, UK
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21
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McCallion O, Bilici M, Hester J, Issa F. Regulatory T-cell therapy approaches. Clin Exp Immunol 2023; 211:96-107. [PMID: 35960852 PMCID: PMC10019137 DOI: 10.1093/cei/uxac078] [Citation(s) in RCA: 20] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2022] [Revised: 07/26/2022] [Accepted: 08/10/2022] [Indexed: 11/13/2022] Open
Abstract
Regulatory T cells (Tregs) have enormous therapeutic potential to treat a variety of immunopathologies characterized by aberrant immune activation. Adoptive transfer of ex vivo expanded autologous Tregs continues to progress through mid- to late-phase clinical trials in several disease spaces and has generated promising preliminary safety and efficacy signals to date. However, the practicalities of this strategy outside of the clinical trial setting remain challenging. Here, we review the current landscape of regulatory T-cell therapy, considering emergent approaches and technologies presenting novel ways to engage Tregs, and reflect on the progress necessary to deliver their therapeutic potential to patients.
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Affiliation(s)
- Oliver McCallion
- Translational Research Immunology Group, Nuffield Department of Surgical Sciences, University of Oxford, Oxford, UK
| | - Merve Bilici
- Translational Research Immunology Group, Nuffield Department of Surgical Sciences, University of Oxford, Oxford, UK
| | - Joanna Hester
- Translational Research Immunology Group, Nuffield Department of Surgical Sciences, University of Oxford, Oxford, UK
| | - Fadi Issa
- Correspondence. Fadi Issa, Translational Research Immunology Group, Nuffield Department of Surgical Sciences, University of Oxford, John Radcliffe Hospital, Headley Way, Oxford OX3 9DU, UK.
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22
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Sugiyama D, Hinohara K, Nishikawa H. Significance of regulatory T cells in cancer immunology and immunotherapy. Exp Dermatol 2023; 32:256-263. [PMID: 36458459 DOI: 10.1111/exd.14721] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2022] [Revised: 11/25/2022] [Accepted: 11/29/2022] [Indexed: 12/03/2022]
Abstract
Immunosuppression in the tumour microenvironment (TME) attenuates antitumor immunity, consequently hindering protective immunosurveillance and preventing effective antitumor immunity induced by cancer immunotherapy. Multiple mechanisms including immune checkpoint molecules, such as CTLA-4, PD-1, and LAG-3, and immunosuppressive cells are involved in the immunosuppression in the TME. Regulatory T (Treg) cells, a population of immunosuppressive cells, play an important role in inhibiting antitumor immunity. Therefore, Treg cells in the TME correlate with an unfavourable prognosis in various cancer types. Thus, Treg cell is considered to become a promising target for cancer immunotherapy. Elucidating Treg cell functions in cancer patients is therefore crucial for developing optimal Treg cell-targeted immunotherapy. Here, we describe Treg cell functions and phenotypes in the TME from the perspective of Treg cell-targeted immunotherapy.
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Affiliation(s)
- Daisuke Sugiyama
- Department of Immunology, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Kunihiko Hinohara
- Department of Immunology, Nagoya University Graduate School of Medicine, Nagoya, Japan
- Institute for Advanced Research, Nagoya University, Nagoya, Japan
| | - Hiroyoshi Nishikawa
- Department of Immunology, Nagoya University Graduate School of Medicine, Nagoya, Japan
- Institute for Advanced Research, Nagoya University, Nagoya, Japan
- Division of Cancer Immunology, Research Institute/Exploratory Oncology Research & Clinical Trial Center (EPOC), National Cancer Center, Chuo-ku, Japan
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23
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Ou Y, Zhan Y, Zhuang X, Shao X, Xu P, Li F, Chen H, Ji L, Cheng Y. A bibliometric analysis of primary immune thrombocytopenia from 2011 to 2021. Br J Haematol 2023; 201:954-970. [PMID: 36807900 DOI: 10.1111/bjh.18692] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2022] [Revised: 01/21/2023] [Accepted: 01/27/2023] [Indexed: 02/22/2023]
Abstract
Primary immune thrombocytopenia (ITP) is an autoimmune disorder characterized by isolated thrombocytopenia. This bibliometric analysis was applied to identify the characteristics of global scientific output, the hotspots, and frontiers of ITP over the past 10 years. We retrieved publications from 2011 to 2021 from the Web of Science Core Collection (WoSCC). Bibliometrix package, VOSviewer, and Citespace were used to analyse and visualize the trend, distribution, and hotspots of research on ITP. Altogether, there were 2084 papers, written by 9080 authors from 410 organizations in 70 countries/regions, published in 456 journals with 37 160 co-cited references. In the last decades, the most productive journal was British Journal of Haematology, China was the most productive country. and the most cited journal was Blood. Shandong University was the most productive institution in the field of ITP. NEUNERT C, 2011, BLOOD, CHENG G, 2011, LANCET, and PATEL VL, 2012, BLOOD were the top three most cited documents. "Thrombopoietin receptor agonist", "regulatory T cell" and "sialic acid" were three hotspots of the last decade. And "immature platelet fraction", "Th17", and "fostamatinib" would be research frontiers in the feature. The present study provided a novel insight for future research directions and scientific decision-making.
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Affiliation(s)
- Yang Ou
- Center for Tumor Diagnosis and Therapy, Jinshan Hospital, Fudan University, Shanghai, China
| | - Yanxia Zhan
- Department of Hematology, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Xibing Zhuang
- Center for Tumor Diagnosis and Therapy, Jinshan Hospital, Fudan University, Shanghai, China.,Department of Hematology, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Xia Shao
- Center for Tumor Diagnosis and Therapy, Jinshan Hospital, Fudan University, Shanghai, China.,Department of Hematology, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Pengcheng Xu
- Center for Tumor Diagnosis and Therapy, Jinshan Hospital, Fudan University, Shanghai, China.,Department of Hematology, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Feng Li
- Department of Hematology, Zhongshan Hospital, Fudan University, Shanghai, China.,Zhongshan Hospital Qingpu Branch, Department of Hematology, Fudan University, Shanghai, China
| | - Hao Chen
- Zhongshan Hospital Xuhui Branch, Department of Thoracic Surgery, Fudan University, Shanghai, China
| | - Lili Ji
- Department of Hematology, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Yunfeng Cheng
- Center for Tumor Diagnosis and Therapy, Jinshan Hospital, Fudan University, Shanghai, China.,Department of Hematology, Zhongshan Hospital, Fudan University, Shanghai, China.,Zhongshan Hospital Qingpu Branch, Department of Hematology, Fudan University, Shanghai, China.,Institute of Clinical Science, Zhongshan Hospital, Fudan University, Shanghai, China
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24
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Huang DL, He YR, Liu YJ, He HY, Gu ZY, Liu YM, Liu WJ, Luo Z, Ju MJ. The immunomodulation role of Th17 and Treg in renal transplantation. Front Immunol 2023; 14:1113560. [PMID: 36817486 PMCID: PMC9928745 DOI: 10.3389/fimmu.2023.1113560] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2022] [Accepted: 01/09/2023] [Indexed: 02/04/2023] Open
Abstract
Kidney transplantation (KT) is an ultimate treatment of end-stage chronic kidney disease, which can meet a lot of complications induced by immune system. With under-controlled immunosuppression, the patient will obtain a good prognosis. Otherwise, allograft disfunction will cause severe organ failure and even immune collapse. Acute or chronic allograft dysfunction after KT is related to Th17, Treg, and Th17/Treg to a certain extent. Elevated Th17 levels may lead to acute rejection or chronic allograft dysfunction. Treg mainly plays a protective role on allografts by regulating immune response. The imbalance of the two may further aggravate the balance of immune response and damage the allograft. Controlling Th17 level, improving Treg function and level, and adjusting Th17/Treg ratio may have positive effects on longer allograft survival and better prognosis of receptors.
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Affiliation(s)
- Dan-Lei Huang
- Department of Critical Care Medicine, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Yi-Ran He
- Department of Critical Care Medicine, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Yu-Jing Liu
- Department of Nursing, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Hong-Yu He
- Department of Critical Care Medicine, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Zhun-Yong Gu
- Department of Urinary Surgery, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Yi-Mei Liu
- Department of Critical Care Medicine, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Wen-Jun Liu
- Department of Critical Care Medicine, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Zhe Luo
- Department of Critical Care Medicine, Zhongshan Hospital, Fudan University, Shanghai, China,*Correspondence: Min-Jie Ju, ; Zhe Luo,
| | - Min-Jie Ju
- Department of Critical Care Medicine, Zhongshan Hospital, Fudan University, Shanghai, China,*Correspondence: Min-Jie Ju, ; Zhe Luo,
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25
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ANGPTL3 deficiency associates with the expansion of regulatory T cells with reduced lipid content. Atherosclerosis 2022; 362:38-46. [PMID: 36253169 DOI: 10.1016/j.atherosclerosis.2022.09.014] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/16/2022] [Revised: 09/20/2022] [Accepted: 09/28/2022] [Indexed: 12/15/2022]
Abstract
BACKGROUND AND AIMS Angiopoietin-like 3 (ANGPTL3) regulates lipid and glucose metabolism. Loss-of-function mutations in its gene, leading to ANGPTL3 deficiency, cause in humans the familial combined hypolipidemia type 2 (FHBL2) phenotype, characterized by very low concentrations of circulating lipoproteins and reduced risk of atherosclerotic cardiovascular disease. Whether this condition is accompanied by immune dysfunctions is unknown. Regulatory T cells (Tregs) are CD4 T lymphocytes endowed with immune suppressive and atheroprotective functions and sensitive to metabolic signals. By investigating FHBL2, we explored the hypothesis that Tregs expand in response to extreme hypolipidemia, through a modulation of the Treg-intrinsic lipid metabolism. METHODS Treg frequency, phenotype, and intracellular lipid content were assessed ex vivo from FHBL2 subjects and age- and sex-matched controls, through multiparameter flow cytometry. The response of CD4 T cells from healthy controls to marked hypolipidemia was tested in vitro in low-lipid culture conditions. RESULTS The ex vivo analysis revealed that FHBL2 subjects showed higher percentages of Tregs with a phenotype undistinguishable from controls and with a lower lipid content, which directly correlated with the concentrations of circulating lipoproteins. In vitro, lipid restriction induced the upregulation of genes of the mevalonate pathway, including those involved in isoprenoid biosynthesis, and concurrently increased the expression of the Treg markers FOXP3 and Helios. The latter event was found to be prenylation-dependent, and likely related to increased IL-2 production and signaling. CONCLUSIONS Our study demonstrates that FHBL2 is characterized by high Treg frequencies, a feature which may concur to the reduced atherosclerotic risk in this condition. Mechanistically, hypolipidemia may directly favor Treg expansion, through the induction of the mevalonate pathway and the prenylation of key signaling proteins.
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26
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Palatella M, Guillaume SM, Linterman MA, Huehn J. The dark side of Tregs during aging. Front Immunol 2022; 13:940705. [PMID: 36016952 PMCID: PMC9398463 DOI: 10.3389/fimmu.2022.940705] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2022] [Accepted: 07/19/2022] [Indexed: 11/13/2022] Open
Abstract
In the last century, we have seen a dramatic rise in the number of older persons globally, a trend known as the grey (or silver) tsunami. People live markedly longer than their predecessors worldwide, due to remarkable changes in their lifestyle and in progresses made by modern medicine. However, the older we become, the more susceptible we are to a series of age-related pathologies, including infections, cancers, autoimmune diseases, and multi-morbidities. Therefore, a key challenge for our modern societies is how to cope with this fragile portion of the population, so that everybody could have the opportunity to live a long and healthy life. From a holistic point of view, aging results from the progressive decline of various systems. Among them, the distinctive age-dependent changes in the immune system contribute to the enhanced frailty of the elderly. One of these affects a population of lymphocytes, known as regulatory T cells (Tregs), as accumulating evidence suggest that there is a significant increase in the frequency of these cells in secondary lymphoid organs (SLOs) of aged animals. Although there are still discrepancies in the literature about modifications to their functional properties during aging, mounting evidence suggests a detrimental role for Tregs in the elderly in the context of bacterial and viral infections by suppressing immune responses against non-self-antigens. Interestingly, Tregs seem to also contribute to the reduced effectiveness of immunizations against many pathogens by limiting the production of vaccine-induced protective antibodies. In this review, we will analyze the current state of understandings about the role of Tregs in acute and chronic infections as well as in vaccination response in both humans and mice. Lastly, we provide an overview of current strategies for Treg modulation with potential future applications to improve the effectiveness of vaccines in older individuals.
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Affiliation(s)
- Martina Palatella
- Department Experimental Immunology, Helmholtz Centre for Infection Research, Braunschweig, Germany
| | | | | | - Jochen Huehn
- Department Experimental Immunology, Helmholtz Centre for Infection Research, Braunschweig, Germany
- Cluster of Excellence RESIST (EXC 2155), Hannover Medical School, Hannover, Germany
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27
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Recent Progress on the Roles of Regulatory T Cells in IgG4-Related Disease. IMMUNO 2022. [DOI: 10.3390/immuno2020026] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Abstract
IgG4-related disease (RD) is a proposed concept of systemic inflammatory condition from Japanese researchers. Patients with IgG4-RD manifest several immunological and histological characterizations in the organs involved, including elevated levels of serum IgG4 and lympho-plasmacytic infiltration, storiform fibrosis, IgG4-positive plasma cells infiltration, and obstructive phlebitis. Nevertheless, the pathogenesis of IgG4-RD still remains unclear. It has been made clear that several immune cells with regulatory function play a vital part in several diseases. In particular, abnormalities in the function and proportion of regulatory T cells (Tregs) are implicated in several diseases, and their part in IgG4-RD has been investigated. This review offers an overview of the research in IgG4-RD related to Tregs. Herein, the basic information of Tregs, knowledge gained from animal models involving Tregs, and the role of IgG4-RD has been provided. We also included the immunological mechanisms of IgG4-RD based on the data accumulated so far in our hypothesis.
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28
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Chen C, Zhang C, Wu B, Xu T. Immune-related adverse events in older adults: Data mining of the FDA Adverse Event Reporting System. J Geriatr Oncol 2022; 13:1017-1022. [PMID: 35660091 DOI: 10.1016/j.jgo.2022.05.009] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2021] [Revised: 03/15/2022] [Accepted: 05/23/2022] [Indexed: 02/08/2023]
Abstract
INTRODUCTION Recent studies reveal that there is no difference in the efficacy of immune checkpoint inhibitors (ICIs) between younger adults and older adults. However, it remains unclear whether age is a risk factor for immune-related adverse events (irAEs). MATERIALS AND METHODS To analyze the association between irAEs and age based on data from the Food and Drug Administration Adverse Event Reporting System (FAERS) database between January 2004 and December 2020, we performed a case/noncase study on ICI-related adverse events. Cases were defined as adverse event cases with ICI therapy and irAEs, and noncases were defined as adverse event cases with ICI therapy and without irAEs. One case was matched to a noncase using the sex, reporter, report year, and type of ICI regimen. The reporting odds ratios (RORs) were used to assess the disproportionality of irAEs between older adults (≥65 years) and younger adults (<65 years). RESULTS The study shows that compared with younger adults, the ROR of older adults was 1.12 (95% confidence interval [CI]: 1.08-1.16) and 1.18 (95% CI: 1.14-1.23) before and after matching, respectively. The signal of age-related irAEs was detected in patients treated with ICI monotherapy but not in patients treated with combination therapy. Further analysis revealed a spectrum of age-related toxicities including cardiovascular toxicities, lung toxicities, musculoskeletal toxicities, nervous system toxicities, renal toxicities, and skin toxicities. CONCLUSION In this analysis performed based on the FAERS, irAE cases were more likely to be reported in older adults. Our pharmacovigilance study complements the safety data of clinical trials. Further studies are expected to explore the underlying reasons for irAEs in older adults.
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Affiliation(s)
- Chen Chen
- Department of Pharmacy, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China; West China School of Pharmacy, Sichuan University, Chengdu, Sichuan 610041, China
| | - Chenyu Zhang
- Department of Pharmacy, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China; West China School of Pharmacy, Sichuan University, Chengdu, Sichuan 610041, China
| | - Bin Wu
- Department of Pharmacy, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China; West China School of Pharmacy, Sichuan University, Chengdu, Sichuan 610041, China.
| | - Ting Xu
- Department of Pharmacy, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China; West China School of Pharmacy, Sichuan University, Chengdu, Sichuan 610041, China
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29
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Pinto BF, Medeiros NI, Teixeira-Carvalho A, Fiuza JA, Eloi-Santos SM, Nunes MCP, Silva SA, Fontes-Cal TCM, Belchior-Bezerra M, Dutra WO, Correa-Oliveira R, Gomes JAS. Modulation of Regulatory T Cells Activity by Distinct CD80 and CD86 Interactions With CD28/CTLA-4 in Chagas Cardiomyopathy. Front Cardiovasc Med 2022; 9:750876. [PMID: 35665256 PMCID: PMC9162138 DOI: 10.3389/fcvm.2022.750876] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2021] [Accepted: 04/08/2022] [Indexed: 11/16/2022] Open
Abstract
Chagas cardiomyopathy is the symptomatic cardiac clinical form (CARD) of the chronic phase of Chagas disease caused by Trypanosoma cruzi infection. It was described as the most fibrosing cardiomyopathies, affecting approximately 30% of patients during the chronic phase. Other less frequent symptomatic clinical forms have also been described. However, most patients who progress to the chronic form develop the indeterminate clinical form (IND), may remain asymptomatic for life, or develop some cardiac damage. Some mechanisms involved in the etiology of the clinical forms of Chagas disease have been investigated. To characterize the contribution of CD80 and CD86 co-stimulatory molecules in the activation of different CD4+ (Th1, Th2, Th17, and Treg) and CD8+ T lymphocyte subsets, we used blocking antibodies for CD80 and CD86 receptors of peripheral blood mononuclear cells (PBMC) in cultures with T. cruzi antigens from non-infected (NI), IND, and CARD individuals. We demonstrated a higher frequency of CD8+ CD25+ T lymphocytes and CD8+ Treg cells after anti-CD80 antibody blockade only in the CARD group. In contrast, a lower frequency of CD4+ Treg lymphocytes after anti-CD86 antibody blockade was found only in IND patients. A higher frequency of CD4+ Treg CD28+ lymphocytes, as well as an association between CD4+ Treg lymphocytes and CD28+ expression on CD4+ Treg cells in the CARD group, but not in IND patients, and once again only after anti-CD80 antibody blockade, was observed. We proposed that Treg cells from IND patients could be activated via CD86-CTLA-4 interaction, leading to modulation of the immune response only in asymptomatic patients with Chagas disease, while CD80 may be involved in the proliferation control of T CD8+ lymphocytes, as also in the modulation of regulatory cell activation via CD28 receptor. For the first time, our data highlight the role of CD80 in modulation of Treg lymphocytes activation in patients with CARD, highlighting a key molecule in the development of Chagas cardiomyopathy.
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Affiliation(s)
- Bruna F. Pinto
- Departamento de Morfologia, Laboratório de Biologia das Interações Celulares, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil
| | - Nayara I. Medeiros
- Departamento de Morfologia, Laboratório de Biologia das Interações Celulares, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil
- Instituto René Rachou, Fundação Oswaldo Cruz–FIOCRUZ, Belo Horizonte, Brazil
| | | | - Jacqueline A. Fiuza
- Instituto René Rachou, Fundação Oswaldo Cruz–FIOCRUZ, Belo Horizonte, Brazil
| | | | - Maria C. P. Nunes
- Departamento de Clínica Médica, Faculdade de Medicina, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil
| | - Silvana A. Silva
- Departamento de Clínica Médica, Faculdade de Medicina, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil
| | - Tereza C. M. Fontes-Cal
- Departamento de Morfologia, Laboratório de Biologia das Interações Celulares, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil
| | - Mayara Belchior-Bezerra
- Departamento de Morfologia, Laboratório de Biologia das Interações Celulares, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil
| | - Walderez O. Dutra
- Departamento de Morfologia, Laboratório de Biologia das Interações Celulares, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil
- Instituto Nacional de Ciência e Tecnologia Doenças Tropicais, Belo Horizonte, Brazil
| | - Rodrigo Correa-Oliveira
- Instituto René Rachou, Fundação Oswaldo Cruz–FIOCRUZ, Belo Horizonte, Brazil
- Instituto Nacional de Ciência e Tecnologia Doenças Tropicais, Belo Horizonte, Brazil
| | - Juliana A. S. Gomes
- Departamento de Morfologia, Laboratório de Biologia das Interações Celulares, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil
- *Correspondence: Juliana A. S. Gomes,
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Mansour R, Bsat YE, Fadel A, El-Orfali Y, Noun D, Tarek N, Kabbara N, Abboud M, Massaad MJ. Diagnosis and Treatment of a Patient With Severe Combined Immunodeficiency Due to a Novel Homozygous Mutation in the IL-7Rα Chain. Front Immunol 2022; 13:867837. [PMID: 35418989 PMCID: PMC8996178 DOI: 10.3389/fimmu.2022.867837] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2022] [Accepted: 03/04/2022] [Indexed: 11/13/2022] Open
Abstract
The interleukin-7 receptor (IL-7R) is expressed on lymphoid cells and plays an important role in the development, homeostasis, survival, and proliferation of T cells. Bi-allelic mutations in the IL-7Rα chain abolish T cell development and function resulting in severe combined immunodeficiency disease. In this manuscript, we investigate a 1 year-old patient born to consanguineous parents, who suffered from autoimmune hemolytic anemia since birth associated with recurrent severe infections. Flow cytometric analysis of the patient’s peripheral blood demonstrated elevated numbers of B and NK cells, decreased numbers of T cells, defective thymic output, a predominance of memory T cells, and absent T cell proliferation. Next Generation Sequencing identified a novel homozygous pathogenic mutation in IL7RA (c.379G>A) that resulted in aberrant IL7RA RNA splicing and absent IL-7Rα expression. The patient was successfully transplanted using her HLA-matched relative as donor. One year after transplant, the patient is clinically stable with normal reconstitution of donor T cells that express IL-7Rα, a significant increase in the percentages of recent thymic emigrant and peripheral T cells, normalization of naïve and memory T cells, and restoration of her T cell’s proliferative response. Therefore, using genetic and functional approaches, we identified a novel deleterious mutation in IL-7Rα that results in T-B+NK+ phenotype, and report successful hematopoietic stem cell transplantation of the patient. This represents the first bedside-to-bench-and-back case entirely performed on a patient with severe combined immunodeficiency at the American University of Beirut Medical Center.
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Affiliation(s)
- Rana Mansour
- Department of Experimental Pathology, Immunology, and Microbiology, Faculty of Medicine, American University of Beirut, Beirut, Lebanon
| | - Yasmin El Bsat
- Department of Experimental Pathology, Immunology, and Microbiology, Faculty of Medicine, American University of Beirut, Beirut, Lebanon
| | - Anthony Fadel
- Faculty of Medicine, American University of Beirut, Beirut, Lebanon
| | - Youmna El-Orfali
- Department of Experimental Pathology, Immunology, and Microbiology, Faculty of Medicine, American University of Beirut, Beirut, Lebanon
| | - Dolly Noun
- Division of Pediatric Hematology Oncology, Department of Pediatrics and Adolescent Medicine, American University of Beirut Medical Center, Beirut, Lebanon.,Children's Cancer Center of Lebanon, American University of Beirut Medical Center, Beirut, Lebanon
| | - Nidale Tarek
- Division of Pediatric Hematology Oncology, Department of Pediatrics and Adolescent Medicine, American University of Beirut Medical Center, Beirut, Lebanon.,Children's Cancer Center of Lebanon, American University of Beirut Medical Center, Beirut, Lebanon
| | - Nabil Kabbara
- Division of Pediatric Hematology Oncology, Rafic Hariri University Hospital, Beirut, Lebanon.,Division of Pediatric Hematology Oncology, Centre Hospitalier du Nord, Zgharta, Lebanon
| | - Miguel Abboud
- Division of Pediatric Hematology Oncology, Department of Pediatrics and Adolescent Medicine, American University of Beirut Medical Center, Beirut, Lebanon.,Children's Cancer Center of Lebanon, American University of Beirut Medical Center, Beirut, Lebanon
| | - Michel J Massaad
- Department of Experimental Pathology, Immunology, and Microbiology, Faculty of Medicine, American University of Beirut, Beirut, Lebanon.,Department of Pediatrics and Adolescent Medicine, American University of Beirut Medical Center, Beirut, Lebanon.,Research Center of Excellence in Immunity and Infections, American University of Beirut, Beirut, Lebanon.,Center for Infectious Diseases Research, American University of Beirut, Beirut, Lebanon
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31
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Revisiting the melanomagenic pathways and current therapeutic approaches. Mol Biol Rep 2022; 49:9651-9671. [DOI: 10.1007/s11033-022-07412-2] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2021] [Accepted: 03/22/2022] [Indexed: 01/10/2023]
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Reinhardt J, Sharma V, Stavridou A, Lindner A, Reinhardt S, Petzold A, Lesche M, Rost F, Bonifacio E, Eugster A. Distinguishing activated T regulatory cell and T conventional cells by single cell technologies. Immunology 2022; 166:121-137. [PMID: 35196398 PMCID: PMC9426617 DOI: 10.1111/imm.13460] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2021] [Revised: 02/09/2022] [Accepted: 02/09/2022] [Indexed: 12/02/2022] Open
Abstract
Resting conventional T cells (Tconv) can be distinguished from T regulatory cells (Treg) by the canonical markers FOXP3, CD25 and CD127. However, the expression of these proteins alters after T‐cell activation leading to overlap between Tconv and Treg. The objective of this study was to distinguish resting and antigen‐responsive T effector (Tconv) and Treg using single‐cell technologies. CD4+ Treg and Tconv cells were stimulated with antigen and responsive and non‐responsive populations processed for targeted and non‐targeted single‐cell RNAseq. Machine learning was used to generate a limited set of genes that could distinguish responding and non‐responding Treg and Tconv cells and which was used for single‐cell multiplex qPCR and to design a flow cytometry panel. Targeted scRNAseq clearly distinguished the four‐cell populations. A minimal set of 27 genes was identified by machine learning algorithms to provide discrimination of the four populations at >95% accuracy. In all, 15 of the genes were validated to be differentially expressed by single‐cell multiplex qPCR. Discrimination of responding Treg from responding Tconv could be achieved by a flow cytometry strategy that included staining for CD25, CD127, FOXP3, IKZF2, ITGA4, and the novel marker TRIM which was strongly expressed in Tconv and weakly expressed in both responding and non‐responding Treg. A minimal set of genes was identified that discriminates responding and non‐responding CD4+ Treg and Tconv cells and, which have identified TRIM as a marker to distinguish Treg by flow cytometry.
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Affiliation(s)
- Julia Reinhardt
- Center for Regenerative Therapies Dresden, Faculty of Medicine, TU Dresden, Dresden, Germany
| | - Virag Sharma
- Center for Regenerative Therapies Dresden, Faculty of Medicine, TU Dresden, Dresden, Germany.,German Center for Diabetes Research (DZD), Paul Langerhans Institute Dresden of Helmholtz Centre Munich at University Clinic Carl Gustav Carus of TU, Faculty of Medicine, Dresden, Germany
| | - Antigoni Stavridou
- Center for Regenerative Therapies Dresden, Faculty of Medicine, TU Dresden, Dresden, Germany
| | - Annett Lindner
- Center for Regenerative Therapies Dresden, Faculty of Medicine, TU Dresden, Dresden, Germany.,German Center for Diabetes Research (DZD), Paul Langerhans Institute Dresden of Helmholtz Centre Munich at University Clinic Carl Gustav Carus of TU, Faculty of Medicine, Dresden, Germany
| | - Susanne Reinhardt
- Technische Universität Dresden, Center for Molecular and Cellular Bioengineering (CMCB), DRESDEN-concept Genome Center, Dresden, Germany
| | - Andreas Petzold
- Technische Universität Dresden, Center for Molecular and Cellular Bioengineering (CMCB), DRESDEN-concept Genome Center, Dresden, Germany
| | - Mathias Lesche
- Technische Universität Dresden, Center for Molecular and Cellular Bioengineering (CMCB), DRESDEN-concept Genome Center, Dresden, Germany
| | - Fabian Rost
- Center for Regenerative Therapies Dresden, Faculty of Medicine, TU Dresden, Dresden, Germany.,Center for Information Services and High-Performance Computing (ZIH), TU Dresden, Dresden, 01062, Germany
| | - Ezio Bonifacio
- Center for Regenerative Therapies Dresden, Faculty of Medicine, TU Dresden, Dresden, Germany.,German Center for Diabetes Research (DZD), Paul Langerhans Institute Dresden of Helmholtz Centre Munich at University Clinic Carl Gustav Carus of TU, Faculty of Medicine, Dresden, Germany
| | - Anne Eugster
- Center for Regenerative Therapies Dresden, Faculty of Medicine, TU Dresden, Dresden, Germany
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Differences of Circulating CD25hi Bregs and Their Correlations with CD4 Effector and Regulatory T Cells in Autoantibody-Positive T1D Compared with Age-Matched Healthy Individuals. J Immunol Res 2022; 2022:2269237. [PMID: 35083339 PMCID: PMC8786465 DOI: 10.1155/2022/2269237] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2021] [Revised: 11/23/2021] [Accepted: 12/11/2021] [Indexed: 11/17/2022] Open
Abstract
Circulating CD25hi B cells, a subset of regulatory B cells in humans, are closely related to inflammation and autoimmune diseases. This study is aimed at investigating the alternation of CD25hi Bregs and their correlation with CD4 effector and regulatory T cells in T1D individuals. We included 68 autoantibody-positive T1D and 68 age-matched healthy individuals with peripheral blood mononuclear cells (PBMCs) and assessed them with CD25hi Bregs and CD4 effector or regulatory T cells by flow cytometry. Here, we demonstrate that the frequency of CD25hi Bregs was significantly decreased in T1D subjects (P = 0.0016), but they were not affected by disease status (age at T1D diagnosis or duration) or T1D risk loci (rs2104286 or rs12251307) in IL2RA (all P > 0.05). Moreover, higher IgD (P = 0.043) and lower CD27 (P = 0.0003) expression was observed in CD25hi Bregs of T1D individuals, but not the expression of IgM, CD24, or CD38 (all P > 0.05). Although there was no correlation between CD25hi Bregs and CD4 effector T cell subsets in either T1D or healthy individuals (all P > 0.05), we found a positive correlation between CD25hi Bregs and CD4 Tregs in healthy controls (Sp. r = 0.3544, P = 0.0249), which disappeared in T1D subjects (Sp. r = 0.137, P = 0.401). In conclusion, our results suggest that decreased CD25hi Bregs and alternation of their phenotypes are features of T1D regardless of disease duration and T1D genetic risk loci, and an impaired balance between CD25hi Bregs and CD4 Tregs might contribute to the pathogenesis of T1D.
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Fang J, Yu L, Zhuang LG, Pei XY, Wang Q, Jin GX. The changes in peripheral blood Th17 and Treg ratios in Hashimoto's thyroiditis are accompanied by differential PD-1/PD-L1 expression. Front Endocrinol (Lausanne) 2022; 13:959477. [PMID: 36093111 PMCID: PMC9454193 DOI: 10.3389/fendo.2022.959477] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/01/2022] [Accepted: 08/08/2022] [Indexed: 11/13/2022] Open
Abstract
OBJECTIVE The aim of this study was to analyze the percentages of T helper 17 cells (Th17s) and T regulatory cells (Tregs) in autoimmune Hashimoto's thyroiditis (HT), and the expression of the checkpoint molecules programmed death receptor 1/programmed death ligand 1 (PD-1/PD-L1) on these cells. METHODS This is a case-control study involving 53 initially diagnosed HT patients (HT group) and 21 normal controls (NC group). The peripheral blood mononuclear cells from the individuals of the two groups were isolated and restimulated ex vivo; the percentage of Th17s, Tregs, PD-1+ Th17s, PD-L1+ Th17s, PD-1+ Tregs, and PD-L1+ Tregs was assessed by flow cytometric analysis. RESULTS (1) The percentage of Th17s in the peripheral blood of the HT group was significantly higher than that of the NC group [(6.38 ± 1.32)% versus (3.12 ± 0.66)%; t = 14.110, P < 0.001], while the percentage of peripheral blood Tregs was significantly lower [(3.82 ± 1.48)% versus (5.61 ± 1.60)%; t = -4.599, P < 0.001]. (2) HT patients' Th17s expressed PD-1 at a significantly lower frequency than their counterparts in the NC [(6.46 ± 2.77)% versus (18.51 ± 3.96)%; t = -14.842, P < 0.001], while no difference was observed for PD-L1 between the two groups. (3) In contrast, both PD-1 and PD-L1 were expressed at significantly higher frequency on HT patients' Tregs than on NC [respectively: (17.01 ± 3.04)% versus (10.23 ± 2.77)%; t = 8.850, P < 0.001 for PD-1; (16.60 ± 9.58)% versus (11.36 ± 10.14)%; t = 2.089, P < 0.005, for PD-L1]. CONCLUSION (1) The increased percentage of Th17s and decreased percentage of PD-1+ Th17s in the HT group suggest that a loss of control on Th17 activity through the checkpoint inhibitory axis PD-1/PD-L1 may participate in disease pathogenesis. (2) While the decreased percentage of Tregs in HT patients may explain a lack of regulatory functions able to prevent the autoimmune destruction of the thyroid, the significance of the increased frequency of Tregs expressing PD-1 and PD-L1, previously reported to boost Tregs differentiation, remains to be established. Elucidating this apparent contradiction may reveal important mechanisms underlying HT pathogenesis.
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35
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Blinova VG, Gladilina YA, Eliseeva DD, Lobaeva TA, Zhdanov DD. [Increased suppressor activity of transformed ex vivo regulatory T-cells in comparison with unstimulated cells of the same donor]. BIOMEDITSINSKAIA KHIMIIA 2022; 68:55-67. [PMID: 35221297 DOI: 10.18097/pbmc20226801055] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/14/2023]
Abstract
Regulatory T-cells CD4⁺CD25⁺FoxP3⁺CD127low (Tregs) play a key role in the maintenance of tolerance to auto antigens, inhibit function of effector T and B lymphocytes, and provide a balance between effector and regulatory arms of immunity. Patients with autoimmune diseases have decreased Treg numbers and impaired suppressive activity. Transformed ex vivo autologous Tregs could restore destroyed balance of the immune system. We developed a method for Treg precursor cell cultivation. Following the method, we were able to grown up 300-400 million of Tregs cells from 50 ml of peripheral blood during a week. Transformed ex vivo Tregs are 90-95% CD4⁺CD25⁺FoxP3⁺CD127low and have increased expression of transcription genes FoxP3 and Helios. Transformed ex vivo Tregs have increased demethylation of FoxP3 promoter and activated genes of proliferation markers Cycline B1, Ki67 and LGALS 1. Transformed ex vivo Tregs have increased suppressive activity and up to 80-90% these cells secrete cytokines TNFα и IFNγ. Our data suggest transformed ex vivo autologous Tregs have genetic, immunophenotypic and functional characteristics for regulatory T-cells and further can be used for adoptive immunotherapy autoimmune diseases and inhibition of transplantation immunity.
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Affiliation(s)
- V G Blinova
- Institute of Biomedical Chemistry, Moscow, Russia
| | | | | | - T A Lobaeva
- Department of Biochemistry, Peoples Friendship University of Russia (RUDN University), Moscow, Russia
| | - D D Zhdanov
- Institute of Biomedical Chemistry, Moscow, Russia; Department of Biochemistry, Peoples Friendship University of Russia (RUDN University), Moscow, Russia
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36
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Dapash M, Castro B, Hou D, Lee-Chang C. Current Immunotherapeutic Strategies for the Treatment of Glioblastoma. Cancers (Basel) 2021; 13:4548. [PMID: 34572775 PMCID: PMC8467991 DOI: 10.3390/cancers13184548] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2021] [Revised: 08/24/2021] [Accepted: 08/24/2021] [Indexed: 12/17/2022] Open
Abstract
Glioblastoma (GBM) is a lethal primary brain tumor. Despite extensive effort in basic, translational, and clinical research, the treatment outcomes for patients with GBM are virtually unchanged over the past 15 years. GBM is one of the most immunologically "cold" tumors, in which cytotoxic T-cell infiltration is minimal, and myeloid infiltration predominates. This is due to the profound immunosuppressive nature of GBM, a tumor microenvironment that is metabolically challenging for immune cells, and the low mutational burden of GBMs. Together, these GBM characteristics contribute to the poor results obtained from immunotherapy. However, as indicated by an ongoing and expanding number of clinical trials, and despite the mostly disappointing results to date, immunotherapy remains a conceptually attractive approach for treating GBM. Checkpoint inhibitors, various vaccination strategies, and CAR T-cell therapy serve as some of the most investigated immunotherapeutic strategies. This review article aims to provide a general overview of the current state of glioblastoma immunotherapy. Information was compiled through a literature search conducted on PubMed and clinical trials between 1961 to 2021.
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Affiliation(s)
- Mark Dapash
- Pritzker School of Medicine, University of Chicago, Chicago, IL 60637, USA;
- Department of Neurological Surgery, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA; (B.C.); (D.H.)
| | - Brandyn Castro
- Department of Neurological Surgery, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA; (B.C.); (D.H.)
- Department of Neurosurgery, University of Chicago, Chicago, IL 60637, USA
| | - David Hou
- Department of Neurological Surgery, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA; (B.C.); (D.H.)
| | - Catalina Lee-Chang
- Department of Neurological Surgery, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA; (B.C.); (D.H.)
- Northwestern Medicine Malnati Brain Tumor Institute, Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA
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Hariyanto AD, Permata TBM, Gondhowiardjo SA. Role of CD4 +CD25 +FOXP3 + T Reg cells on tumor immunity. Immunol Med 2021; 45:94-107. [PMID: 34495808 DOI: 10.1080/25785826.2021.1975228] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022] Open
Abstract
Not all T cells are effector cells of the anti-tumor immune system. One of the subpopulations of CD4+ T cells that express CD25+ and the transcription factor FOXP3, known as Regulator T cells (TReg), plays an essential role in maintaining tolerance and immune homeostasis preventing autoimmune diseases, minimalize chronic inflammatory diseases by enlisting various immunoregulatory mechanisms. The balance between effector T cells (Teff) and regulator T cells is crucial in determining the outcome of an immune response. Regarding tumors, activation or expansion of TReg cells reduces anti-tumor immunity. TReg cells inhibit the activation of CD4+ and CD8+ T cells and suppress anti-tumor activity in the tumor microenvironment. In addition, TReg cells also promote tumor angiogenesis both directly and indirectly to ensure oxygen and nutrient transport to the tumor. There is accumulating evidence showing a positive result that removing or suppressing TReg cells increases anti-tumor immune response. However, depletion of TReg cells will cause autoimmunity. One strategy to improve or restore tumor immunity is targeted therapy on the dominant effector TReg cells in tumor tissue. Various molecules such as CTLA-4, CD4, CD25, GITR, PD-1, OX40, ICOS are in clinical trials to assess their role in attenuating TReg cells' function.
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Affiliation(s)
- Agustinus Darmadi Hariyanto
- Faculty of Medicine, Department of Radiotherapy, Universitas Indonesia/Cipto Mangunkusumo National General Hospital, Jakarta, Indonesia
| | - Tiara Bunga Mayang Permata
- Faculty of Medicine, Department of Radiotherapy, Universitas Indonesia/Cipto Mangunkusumo National General Hospital, Jakarta, Indonesia
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Karachi A, Dastmalchi F, Nazarian S, Huang J, Sayour EJ, Jin L, Yang C, Mitchell DA, Rahman M. Optimizing T Cell-Based Therapy for Glioblastoma. Front Immunol 2021; 12:705580. [PMID: 34421912 PMCID: PMC8374079 DOI: 10.3389/fimmu.2021.705580] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2021] [Accepted: 07/20/2021] [Indexed: 11/30/2022] Open
Abstract
Evading T cell surveillance is a hallmark of cancer. Patients with solid tissue malignancy, such as glioblastoma (GBM), have multiple forms of immune dysfunction, including defective T cell function. T cell dysfunction is exacerbated by standard treatment strategies such as steroids, chemotherapy, and radiation. Reinvigoration of T cell responses can be achieved by utilizing adoptively transferred T cells, including CAR T cells. However, these cells are at risk for depletion and dysfunction as well. This review will discuss adoptive T cell transfer strategies and methods to avoid T cell dysfunction for the treatment of brain cancer.
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Affiliation(s)
- Aida Karachi
- Lillian S. Wells Department of Neurosurgery, University of Florida (UF) Brain Tumor Immunotherapy Program, University of Florida, Gainesville, FL, United States
| | - Farhad Dastmalchi
- Lillian S. Wells Department of Neurosurgery, University of Florida (UF) Brain Tumor Immunotherapy Program, University of Florida, Gainesville, FL, United States
| | - Saina Nazarian
- Lillian S. Wells Department of Neurosurgery, University of Florida (UF) Brain Tumor Immunotherapy Program, University of Florida, Gainesville, FL, United States
| | - Jianping Huang
- Lillian S. Wells Department of Neurosurgery, University of Florida (UF) Brain Tumor Immunotherapy Program, University of Florida, Gainesville, FL, United States
| | - Elias J Sayour
- Lillian S. Wells Department of Neurosurgery, University of Florida (UF) Brain Tumor Immunotherapy Program, University of Florida, Gainesville, FL, United States
| | - Linchun Jin
- Lillian S. Wells Department of Neurosurgery, University of Florida (UF) Brain Tumor Immunotherapy Program, University of Florida, Gainesville, FL, United States
| | - Changlin Yang
- Lillian S. Wells Department of Neurosurgery, University of Florida (UF) Brain Tumor Immunotherapy Program, University of Florida, Gainesville, FL, United States
| | - Duane A Mitchell
- Lillian S. Wells Department of Neurosurgery, University of Florida (UF) Brain Tumor Immunotherapy Program, University of Florida, Gainesville, FL, United States
| | - Maryam Rahman
- Lillian S. Wells Department of Neurosurgery, University of Florida (UF) Brain Tumor Immunotherapy Program, University of Florida, Gainesville, FL, United States
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Yang YW, Chen CC, Yang CY, Lee CY, Yang HC, Chiang BL, Chuang YH, Wu TE, Lai HS, Tsai MK. Dynamics of cellular immune responses in recipients of renal allografts positive for hepatitis B surface antigen. J Formos Med Assoc 2021; 121:958-968. [PMID: 34294497 DOI: 10.1016/j.jfma.2021.07.008] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2020] [Revised: 05/27/2021] [Accepted: 07/06/2021] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND/PURPOSE Hepatitis B surface antigen (HBsAg)-positive renal transplantation recipients must take lifelong immunosuppressants and nucleotide analogues (NAs). We investigated the cellular immune responses of HBsAg-positive renal transplantation recipients taking immunosuppressants and NAs. METHODS Blood samples were collected from HBsAg-positive individuals with end-stage renal disease on the transplant waiting list (Group 1) and renal transplantation recipients taking immunosuppressants and NAs (Group 2) or immunosuppressants without NAs (Group 3). Hepatitis B virus (HBV)-specific pentamers were used to quantify circulating HBV-specific CD8+ T cells. RESULTS Groups 2 and 3 had higher cellular immune responses, as indicated by significantly lower regulatory T (Treg)/CD8+ T cell ratios than Group 1. With undetectable viral loads under both immunosuppressant and NAs, the CD8+ T cell and HBV-specific CD8+ T cell frequencies were similar in Group 2 and Group 1. Patients in Group 3 did not use NAs and had an elevated viral load and higher HBV-specific CD8+ T cell and IFN-γ-producing HBV-specific CD8+ T cell frequencies, but lower a frequency of programmed death-1 (PD-1)+ HBV-specific CD8+ T cells than the other groups. Increased viral replication in Group 3 resulted in significantly higher CD8+ T cell and IFN-γ-producing CD8+ T cell frequencies than Group 1. CONCLUSIONS Immunosuppressant therapy increases viral replication in HBsAg-positive renal transplant recipients due to disabling or dysregulation of virus-specific CD8+ T cells. The higher cellular immune responses due to lower Treg/CD8+ T cell ratios in HBsAg-positive renal transplant recipients may be one of the reasons to induce liver pathology because of uncontrolled viral replication.
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Affiliation(s)
- Ya-Wen Yang
- Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine, Taipei, Taiwan; Department of Surgery, National Taiwan University Hospital, Taipei, Taiwan
| | - Chien-Chia Chen
- Department of Surgery, National Taiwan University Hospital, Taipei, Taiwan
| | - Ching-Yao Yang
- Department of Surgery, National Taiwan University Hospital, Taipei, Taiwan
| | - Chih-Yuan Lee
- Department of Surgery, National Taiwan University Hospital, Taipei, Taiwan
| | - Hung-Chih Yang
- Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
| | - Bor-Luen Chiang
- Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine, Taipei, Taiwan
| | - Ya-Hui Chuang
- Department of Clinical Laboratory Sciences and Medical Biotechnology, National Taiwan University College of Medicine, Taipei, Taiwan
| | - Tiffany E Wu
- Department of Surgery, National Taiwan University Hospital, Taipei, Taiwan
| | - Hong-Shiee Lai
- Department of Surgery, National Taiwan University Hospital, Taipei, Taiwan; Center for Surgical Development, Buddhist Tzu Chi General Hospital, Hualien, Taiwan.
| | - Meng-Kun Tsai
- Department of Surgery, National Taiwan University Hospital, Taipei, Taiwan; Department of Surgery, National Taiwan University Hospital, Hsin-Chu Branch, Hsin-Chu City, Taiwan.
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40
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Regulatory T cells and vaccine effectiveness in older adults. Challenges and prospects. Int Immunopharmacol 2021; 96:107761. [PMID: 34162139 DOI: 10.1016/j.intimp.2021.107761] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2021] [Revised: 04/24/2021] [Accepted: 05/04/2021] [Indexed: 12/21/2022]
Abstract
Since the discovery of lymphocytes with immunosuppressive activity, increasing interest has arisen in their possible influence on the immune response induced by vaccines. Regulatory T cells (Tregs) are essential for maintaining peripheral tolerance, preventing autoimmune diseases, and limiting chronic inflammatory diseases. However, they also limit beneficial immune responses by suppressing anti-infectious and anti-tumor immunity. Mounting evidence suggests that Tregs are involved, at least in part, in the low effectiveness of immunization against various diseases where it has been difficult to obtain protective vaccines. Interestingly, increased activity of Tregs is associated with aging, suggesting a key role for these cells in the lower vaccine effectiveness observed in older people. In this review, we analyze the impact of Tregs on vaccination, with a focus on older adults. Finally, we address an overview of current strategies for Tregs modulation with potential application to improve the effectiveness of future vaccines targeting older populations.
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41
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Treg-Resistant Cytotoxic CD4 + T Cells Dictate T Helper Cells in Their Vicinity: TH17 Skewing and Modulation of Proliferation. Int J Mol Sci 2021; 22:ijms22115660. [PMID: 34073458 PMCID: PMC8198086 DOI: 10.3390/ijms22115660] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2021] [Revised: 05/19/2021] [Accepted: 05/23/2021] [Indexed: 12/31/2022] Open
Abstract
Cytotoxic CD4+ T cells (CD4 CTL) are terminally differentiated T helper cells that contribute to autoimmune diseases, such as multiple sclerosis. We developed a novel triple co-culture transwell assay to study mutual interactions between CD4 CTL, conventional TH cells, and regulatory T cells (Tregs) simultaneously. We show that, while CD4 CTL are resistant to suppression by Tregs in vitro, the conditioned medium of CD4 CTL accentuates the suppressive phenotype of Tregs by upregulating IL-10, Granzyme B, CTLA-4, and PD-1. We demonstrate that CD4 CTL conditioned medium skews memory TH cells to a TH17 phenotype, suggesting that the CD4 CTL induce bystander polarization. In our triple co-culture assay, the CD4 CTL secretome promotes the proliferation of TH cells, even in the presence of Tregs. However, when cell−cell contact is established between CD4 CTL and TH cells, the proliferation of TH cells is no longer increased and Treg-mediated suppression is restored. Taken together, our results suggest that when TH cells acquire cytotoxic properties, these Treg-resistant CD4 CTL affect the proliferation and phenotype of conventional TH cells in their vicinity. By creating such a pro-inflammatory microenvironment, CD4 CTL may favor their own persistence and expansion, and that of other potentially pathogenic TH cells, thereby contributing to pathogenic responses in autoimmune disorders.
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42
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Zhang Y, Zhang J, Shi Y, Shen M, Lv H, Chen S, Feng Y, Chen H, Xu X, Yang T, Xu K. Differences in Maturation Status and Immune Phenotypes of Circulating Helios + and Helios - Tregs and Their Disrupted Correlations With Monocyte Subsets in Autoantibody-Positive T1D Individuals. Front Immunol 2021; 12:628504. [PMID: 34054801 PMCID: PMC8149963 DOI: 10.3389/fimmu.2021.628504] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2020] [Accepted: 04/22/2021] [Indexed: 12/22/2022] Open
Abstract
CD4 Tregs are involved in the regulation of various autoimmune diseases but believed to be highly heterogeneous. Studies have indicated that Helios controls a distinct subset of functional Tregs. However, the immunological changes in circulating Helios+ and Helios− Tregs are not fully explored in type 1 diabetes (T1D). Here, we elucidated the differences in maturation status and immune regulatory phenotypes of Helios+ and Helios− Tregs and their correlations with monocyte subsets in T1D individuals. As CD25−/low FOXP3+ Tregs also represent a subset of functional Tregs, we defined Tregs as FOXP3+CD127−/low and examined circulating Helios+ and Helios− Treg subpopulations in 68 autoantibody-positive T1D individuals and 68 age-matched healthy controls. We found that expression of both FOXP3 and CTLA4 diminished in Helios− Tregs, while the proportion of CD25−/low Tregs increased in Helios+ Tregs of T1D individuals. Although the frequencies of neither Helios+ nor Helios− Tregs were affected by investigated T1D genetic risk loci, Helios+ Tregs correlated with age at T1D diagnosis negatively and disease duration positively. Moreover, the negative correlation between central and effector memory proportions of Helios+ Tregs in healthy controls was disrupted in T1D individuals. Finally, regulatory non-classical and intermediate monocytes also decreased in T1D individuals, and positive correlations between these regulatory monocytes and Helios+/Helios− Treg subsets in healthy controls disappeared in T1D individuals. In conclusion, we demonstrated the alternations in maturation status and immune phenotypes in Helios+ and Helios− Treg subsets and revealed the missing association between these Treg subsets and monocyte subsets in T1D individuals, which might point out another option for elucidating T1D mechanisms.
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Affiliation(s)
- Yuyue Zhang
- Department of Endocrinology and Metabolism, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Jie Zhang
- Department of Endocrinology and Metabolism, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Yun Shi
- Department of Endocrinology and Metabolism, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Min Shen
- Department of Endocrinology and Metabolism, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Hui Lv
- Department of Endocrinology and Metabolism, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Shu Chen
- Department of Endocrinology and Metabolism, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Yingjie Feng
- Department of Endocrinology and Metabolism, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Heng Chen
- Department of Endocrinology and Metabolism, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Xinyu Xu
- Department of Endocrinology and Metabolism, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Tao Yang
- Department of Endocrinology and Metabolism, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Kuanfeng Xu
- Department of Endocrinology and Metabolism, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
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43
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Small organic molecules accelerate the expansion of regulatory T cells. Bioorg Chem 2021; 111:104908. [PMID: 33895604 DOI: 10.1016/j.bioorg.2021.104908] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2020] [Revised: 04/04/2021] [Accepted: 04/07/2021] [Indexed: 11/21/2022]
Abstract
The regulatory T cells (Treg cells) expressing CD4 + CD25 + FOXP3 + markers are indispensable for the initiation of immune homeostasis and tolerance to self-antigens in both mice and humans. A decrease in regulatory T cells leads to various autoimmune pathologies. Herein, we report three low molecular weight, small organic molecules as a new series of Treg proliferators TRP-1-3. These small molecules were tested for their proliferative effect on regulatory T cells. It was found that TRP-1 (Oleracein E) strongly accelerates the Treg proliferation in vitro in a concentration-dependent manner. The effect was evident for all subsets of Treg cells tested, including naturally occurring, thymus-derived and peripherally-induced or adaptive Treg, indicating an effect independent of the maturation site. Importantly, increased Treg cells numbers by TRP-1 correlated with improved CD4 + CD25 + FOXP3 + expression in vitro, while propidium iodide-based staining showed low TRP-1-induced cytotoxicity. Molecular docking plus simulation studies of these TRP-1-3 with IL-2R, mTOR and TCR receptors suggest a TCR-based Treg cells activation mechanism. Because of its high Treg cells activities and low cellular cytotoxicity, TRP-1-3 may be useful in stimulating ex-vivo/in-vivo, Treg cell-specific responses for therapeutic applications.
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44
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Decipher the Glioblastoma Microenvironment: The First Milestone for New Groundbreaking Therapeutic Strategies. Genes (Basel) 2021; 12:genes12030445. [PMID: 33804731 PMCID: PMC8003887 DOI: 10.3390/genes12030445] [Citation(s) in RCA: 49] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2021] [Revised: 03/12/2021] [Accepted: 03/17/2021] [Indexed: 02/06/2023] Open
Abstract
Glioblastoma (GBM) is the most common primary malignant brain tumour in adults. Despite the combination of novel therapeutical approaches, it remains a deadly malignancy with an abysmal prognosis. GBM is a polymorphic tumour from both molecular and histological points of view. It consists of different malignant cells and various stromal cells, contributing to tumour initiation, progression, and treatment response. GBM’s microenvironment is multifaceted and is made up of soluble factors, extracellular matrix components, tissue-resident cell types (e.g., neurons, astrocytes, endothelial cells, pericytes, and fibroblasts) together with resident (e.g., microglia) or recruited (e.g., bone marrow-derived macrophages) immune cells. These latter constitute the so-called immune microenvironment, accounting for a substantial GBM’s tumour volume. Despite the abundance of immune cells, an intense state of tumour immunosuppression is promoted and developed; this represents the significant challenge for cancer cells’ immune-mediated destruction. Though literature data suggest that distinct GBM’s subtypes harbour differences in their microenvironment, its role in treatment response remains obscure. However, an in-depth investigation of GBM’s microenvironment may lead to novel therapeutic opportunities to improve patients’ outcomes. This review will elucidate the GBM’s microenvironment composition, highlighting the current state of the art in immunotherapy approaches. We will focus on novel strategies of active and passive immunotherapies, including vaccination, gene therapy, checkpoint blockade, and adoptive T-cell therapies.
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45
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Yang P, Tian H, Zou YR, Chambon P, Ichinose H, Honig G, Diamond B, Kim SJ. Epinephrine Production in Th17 Cells and Experimental Autoimmune Encephalitis. Front Immunol 2021; 12:616583. [PMID: 33692790 PMCID: PMC7937652 DOI: 10.3389/fimmu.2021.616583] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2020] [Accepted: 01/05/2021] [Indexed: 12/17/2022] Open
Abstract
Epinephrine is a hormone secreted primarily by medullary cells of the adrenal glands which regulates permeability of blood–brain barrier (BBB). Recent studies showed signaling by epinephrine/epinephrine receptor in T cells is involved in autoimmune diseases. Nevertheless, the production of epinephrine by T cells and its pathogenic function in T cells are not well investigated. Our results show that phenylethanol N-methyltransferase (PNMT), a rate-limiting enzyme of epinephrine synthesis, is specifically expressed in vitro in differentiated TH17 cells and in tissue-resident TH17 cells. Indeed, expression levels of enzymes involved in epinephrine production are higher in TH17 cells from animals after EAE induction. The induction of PNMT was not observed in other effector T cell subsets or regulatory T cells. Epinephrine producing TH17 cells exhibit co-expression of GM-CSF, suggesting they are pathogenic TH17 cells. To delineate the function of epinephrine-production in TH17 cells, we generated a TH17-specific knockout of tyrosine hydroxylase (Th) by breeding a Th-flox and a ROR-gt-CRE mouse (Th-CKO). Th-CKO mice are developmentally normal with an equivalent T lymphocyte number in peripheral lymphoid organs. Th-CKO mice also show an equivalent number of TH17 cells in vivo and following in vitro differentiation. To test whether epinephrine-producing TH17 cells are key for breaching the BBB, migration of T cells through mouse brain endothelial cells was investigated in vitro. Both epi+ wild-type and epi- TH17 cells migrate through an endothelial cell barrier. Mice were immunized with MOG peptide to induce experimental autoimmune encephalitis (EAE) and disease progression was monitored. Although there is a reduced infiltration of CD4+ T cells in Th-CKO mice, no difference in clinical score was observed between Th-CKO and wild-type control mice. Increased neutrophils were observed in the central nervous system of Th-CKO mice, suggesting an alternative pathway to EAE progression in the absence of TH17 derived epinephrine.
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Affiliation(s)
- Pinguang Yang
- Center of Autoimmune and Hematopoietic and Musculoskeletal diseases, The Feinstein Institute for Medical Research, Manhasset, NY, United States.,Donald and Barbara Zucker School of Medicine, Hofstra/Northwell, Hempstead, NY, United States
| | - Hong Tian
- Center of Autoimmune and Hematopoietic and Musculoskeletal diseases, The Feinstein Institute for Medical Research, Manhasset, NY, United States
| | - Yong-Rui Zou
- Center of Autoimmune and Hematopoietic and Musculoskeletal diseases, The Feinstein Institute for Medical Research, Manhasset, NY, United States
| | - Pierre Chambon
- Institute for Genetics and Cellular and Molecular Biology, Institute of Advanced Study of the University of Strasbourg, Strasbourg, France
| | - Hiroshi Ichinose
- Department of Life Science, Graduate School of bioscience and Biotechnology, Tokyo Institute of Technology, Yokohama, Japan
| | - Gerard Honig
- Crohn's & Colitis Foundation, National Headquarters, New York, NY, United States
| | - Betty Diamond
- Center of Autoimmune and Hematopoietic and Musculoskeletal diseases, The Feinstein Institute for Medical Research, Manhasset, NY, United States
| | - Sun Jung Kim
- Center of Autoimmune and Hematopoietic and Musculoskeletal diseases, The Feinstein Institute for Medical Research, Manhasset, NY, United States
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Mandapathil M, Szczepanski M, Harasymczuk M, Ren J, Cheng D, Jackson EK, Gorelik E, Johnson J, Lang S, Whiteside TL. CD26 expression and adenosine deaminase activity in regulatory T cells (Treg) and CD4(+) T effector cells in patients with head and neck squamous cell carcinoma. Oncoimmunology 2021; 1:659-669. [PMID: 22934258 PMCID: PMC3429570 DOI: 10.4161/onci.20387] [Citation(s) in RCA: 56] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Abstract
Adenosine deaminase (ADA) is responsible for the deamination of immunosuppressive adenosine to inosine. In human T lymphocytes, ADA is associated with dipeptidyl peptidase IV (CD26). ADA expression and activity were evaluated in regulatory T cells (Treg) and CD4(+) T effector cells (Teff) of patients with head and neck squamous cell cancer (HNSCC). CD4(+)CD39(+) and CD4(+)CD39(neg) T cells were isolated by single-cell sorting from the peripheral blood of 15 HNSCC patients and 15 healthy donors (NC). CD26/ADA expression in these cells was studied by multicolor flow cytometry, confocal microscopy, RT-PCR and immunohistochemistry in tumor tissues. ADA activity was evaluated by mass spectrometry, suppression of Teff proliferation in CFSE assays and cytokine production by Luminex. CD4(+)CD39(+) Treg had low and CD4(+)CD39(neg) Teff high CD26/ADA expression and ADA activity in NC or HNSCC. The frequency and suppressor activity of CD39(+)CD26(neg) Treg were elevated in patients relative to NC (p < 0.01). However, ADA activity in patients' CD4(+)CD39(neg) Teff was decreased (p < 0.05), resulting in extracellular adenosine accumulation. Also, patients' Teff were more sensitive to inhibitory signals delivered via adenosine receptors. IL-2, IL12 and INFγ upregulated ADA expression and activity in CD4(+)CD39(neg) Teff, whereas IL-10, PGE(2) and CADO downregulated it. The differentially expressed CD26/ADA can serve as surface markers for functionally-active CD39(+)CD26(neg) Treg.
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Affiliation(s)
- Magis Mandapathil
- University of Pittsburgh Cancer Institute; Pittsburgh, PA USA ; Department of Otorhinolaryngology; University of Duisburg-Essen; Essen, Germany
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Nussbaum L, Chen YL, Ogg GS. Role of regulatory T cells in psoriasis pathogenesis and treatment. Br J Dermatol 2021; 184:14-24. [PMID: 32628773 DOI: 10.1111/bjd.19380] [Citation(s) in RCA: 153] [Impact Index Per Article: 38.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/26/2020] [Indexed: 12/14/2022]
Abstract
Psoriasis is a chronic inflammatory disease with a strong genetic component that can be triggered by environmental factors. Disease pathogenesis is mainly driven by type 1 and type 17 cytokine-producing cells which, in healthy individuals, are modulated by regulatory T cells (Tregs). Tregs play a fundamental role in immune homeostasis and contribute to the prevention of autoimmune disease by suppressing immune responses. In psoriasis, Tregs are impaired in their suppressive function leading to an altered T-helper 17/Treg balance. Although Treg dysfunction in patients with psoriasis is associated with disease exacerbation, it is unknown how they are functionally regulated. In this review, we discuss recent insights into Tregs in the setting of psoriasis with an emphasis on the effect of current treatments on Tregs and how already available therapeutics that modulate Treg frequency or functionality could be exploited for treatment of psoriasis.
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Affiliation(s)
- L Nussbaum
- Medical Research Council Human Immunology Unit, Radcliffe Department of Medicine, Oxford National Institute for Health Research Biomedical Research Centre, Medical Research Council Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK
| | - Y L Chen
- Medical Research Council Human Immunology Unit, Radcliffe Department of Medicine, Oxford National Institute for Health Research Biomedical Research Centre, Medical Research Council Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK
| | - G S Ogg
- Medical Research Council Human Immunology Unit, Radcliffe Department of Medicine, Oxford National Institute for Health Research Biomedical Research Centre, Medical Research Council Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK
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48
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Kolb HR, Borcherding N, Zhang W. Understanding and Targeting Human Cancer Regulatory T Cells to Improve Therapy. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2021; 1278:229-256. [PMID: 33523451 DOI: 10.1007/978-981-15-6407-9_12] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Regulatory T cells (Tregs) are critical in maintaining immune homeostasis under various pathophysiological conditions. A growing body of evidence demonstrates that Tregs play an important role in cancer progression and that they do so by suppressing cancer-directed immune responses. Tregs have been targeted for destruction by exploiting antibodies against and small-molecule inhibitors of several molecules that are highly expressed in Tregs-including immune checkpoint molecules, chemokine receptors, and metabolites. To date, these strategies have had only limited antitumor efficacy, yet they have also created significant risk of autoimmunity because most of them do not differentiate Tregs in tumors from those in normal tissues. Currently, immune checkpoint inhibitor (ICI)-based cancer immunotherapies have revolutionized cancer treatment, but the resistance to ICI is common and the elevation of Tregs is one of the most important mechanisms. Therapeutic strategies that can selectively eliminate Tregs in the tumor (i.e. therapies that do not run the risk of causing autoimmunity by affecting normal tissue), are urgently needed for the development of cancer immunotherapies. This chapter discusses specific properties of human Tregs under the context of cancer and the various ways to target Treg for cancer immunotherapy.
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Affiliation(s)
- H Ryan Kolb
- Department of Pathology, Immunology and Laboratory Medicine, University of Florida, Gainesville, FL, USA
| | - Nicholas Borcherding
- Department of Pathology and Immunology, Washington University, St. Louis, MO, USA
| | - Weizhou Zhang
- Department of Pathology, Immunology and Laboratory Medicine, University of Florida, Gainesville, FL, USA.
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49
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Ou A, Yung WKA, Majd N. Molecular Mechanisms of Treatment Resistance in Glioblastoma. Int J Mol Sci 2020; 22:E351. [PMID: 33396284 PMCID: PMC7794986 DOI: 10.3390/ijms22010351] [Citation(s) in RCA: 155] [Impact Index Per Article: 31.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2020] [Revised: 12/25/2020] [Accepted: 12/28/2020] [Indexed: 12/18/2022] Open
Abstract
Glioblastoma is the most common malignant primary brain tumor in adults and is almost invariably fatal. Despite our growing understanding of the various mechanisms underlying treatment failure, the standard-of-care therapy has not changed over the last two decades, signifying a great unmet need. The challenges of treating glioblastoma are many and include inadequate drug or agent delivery across the blood-brain barrier, abundant intra- and intertumoral heterogeneity, redundant signaling pathways, and an immunosuppressive microenvironment. Here, we review the innate and adaptive molecular mechanisms underlying glioblastoma's treatment resistance, emphasizing the intrinsic challenges therapeutic interventions must overcome-namely, the blood-brain barrier, tumoral heterogeneity, and microenvironment-and the mechanisms of resistance to conventional treatments, targeted therapy, and immunotherapy.
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Affiliation(s)
| | - W. K. Alfred Yung
- Department of Neuro-Oncology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd., Unit 431, Houston, TX 77030, USA;
| | - Nazanin Majd
- Department of Neuro-Oncology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd., Unit 431, Houston, TX 77030, USA;
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50
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Chatzileontiadou DSM, Sloane H, Nguyen AT, Gras S, Grant EJ. The Many Faces of CD4 + T Cells: Immunological and Structural Characteristics. Int J Mol Sci 2020; 22:E73. [PMID: 33374787 PMCID: PMC7796221 DOI: 10.3390/ijms22010073] [Citation(s) in RCA: 60] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2020] [Revised: 12/20/2020] [Accepted: 12/21/2020] [Indexed: 12/14/2022] Open
Abstract
As a major arm of the cellular immune response, CD4+ T cells are important in the control and clearance of infections. Primarily described as helpers, CD4+ T cells play an integral role in the development and activation of B cells and CD8+ T cells. CD4+ T cells are incredibly heterogeneous, and can be divided into six main lineages based on distinct profiles, namely T helper 1, 2, 17 and 22 (Th1, Th2, Th17, Th22), regulatory T cells (Treg) and T follicular helper cells (Tfh). Recent advances in structural biology have allowed for a detailed characterisation of the molecular mechanisms that drive CD4+ T cell recognition. In this review, we discuss the defining features of the main human CD4+ T cell lineages and their role in immunity, as well as their structural characteristics underlying their detection of pathogens.
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Affiliation(s)
- Demetra S. M. Chatzileontiadou
- Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Clayton, VIC 3800, Australia; (D.S.M.C.); (H.S.); (A.T.N.); (S.G.)
| | - Hannah Sloane
- Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Clayton, VIC 3800, Australia; (D.S.M.C.); (H.S.); (A.T.N.); (S.G.)
| | - Andrea T. Nguyen
- Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Clayton, VIC 3800, Australia; (D.S.M.C.); (H.S.); (A.T.N.); (S.G.)
| | - Stephanie Gras
- Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Clayton, VIC 3800, Australia; (D.S.M.C.); (H.S.); (A.T.N.); (S.G.)
- Australian Research Council Centre of Excellence for Advanced Molecular Imaging, Monash University, Clayton, VIC 3800, Australia
| | - Emma J. Grant
- Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Clayton, VIC 3800, Australia; (D.S.M.C.); (H.S.); (A.T.N.); (S.G.)
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