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Ali A, Younas K, Khatoon A, Murtaza B, Ji Z, Akbar K, Tanveer Q, Bahadur SUK, Su Z. Immune watchdogs: Tissue-resident lymphocytes as key players in cancer defense. Crit Rev Oncol Hematol 2025; 208:104644. [PMID: 39900319 DOI: 10.1016/j.critrevonc.2025.104644] [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: 10/30/2024] [Revised: 01/27/2025] [Accepted: 01/29/2025] [Indexed: 02/05/2025] Open
Abstract
Tissue-resident lymphocytes play a crucial role in immune surveillance against cancer, yet their complex interactions and regulatory pathways remain underexplored, highlighting the need for a deeper understanding to enhance cancer immunotherapy strategies. Lymphocytes across the range of innate-adaptive responses can establish long-lasting presence in tissues, exerting a vital function in the local immune response against diverse antigens. These tissue-resident lymphocytes identify antigens and alarmins secreted by microbial infections and non-infectious stresses at barrier locations by closely interacting with epithelial and endothelial cells. Then they initiate effector responses to restore tissue homeostasis. Significantly, this immune defense system has been demonstrated to monitor the processes of epithelial cell transformation, carcinoma advancement, and cancer metastasis at remote locations, so establishing it as an essential element of cancer immunological surveillance. This review aims to elucidate the roles of diverse tissue-resident lymphocyte populations in shaping cancer immune responses and to investigate their synergistic effector mechanisms for advancing cancer immunotherapy.
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Affiliation(s)
- Ashiq Ali
- Department of Histology and Embryology, Shantou University Medical College, Shantou, China.
| | - Khadija Younas
- Department of Theriogenology, University of Agriculture, Faisalabad, Pakistan
| | - Aisha Khatoon
- Department of Pathology, University of Agriculture, Faisalabad, Pakistan
| | - Bilal Murtaza
- Dalian University of Science and Technology, Dalian, China
| | - Ziyi Ji
- Department of Histology and Embryology, Shantou University Medical College, Shantou, China
| | - Kaynaat Akbar
- Department of Zoology, Wildlife and Fisheries, Faculty of Sciences, University of Agriculture, Faisalabad, Pakistan
| | - Qaisar Tanveer
- The Roslin Institute, The Royal (Dick) School of Veterinary Studies, The University of Edinburgh, EH25 9RG, UK
| | - Sami Ullah Khan Bahadur
- College of Veterinary Medicine and Biomedical Sciences, Colorado State University, Fort Colins, CO 80523, USA
| | - Zhongjing Su
- Department of Histology and Embryology, Shantou University Medical College, Shantou, China.
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2
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Golzari-Sorkheh M, Yoganathan K, Chen ELY, Singh J, Zúñiga-Pflücker JC. T Cell Development: From T-Lineage Specification to Intrathymic Maturation. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2025; 1471:81-137. [PMID: 40067585 DOI: 10.1007/978-3-031-77921-3_4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/13/2025]
Abstract
T cell development occurs in the thymus in both mice and humans. Upon entry into the thymus, bone marrow-derived blood-borne progenitors receive instructive signals, including Notch signaling, to eliminate their potential to develop into alternative immune lineages while committing to the T cell fate. Upon T-lineage commitment, developing T cells receive further instructional cues to generate different T cell sublineages, which together possess diverse immunological functions to provide host immunity. Over the years, numerous studies have contributed to a greater understanding of key thymic signals that govern T cell differentiation and subset generation. Here, we review these critical signaling factors that govern the different stages of both mouse and human T cell development, while also focusing on the transcriptional changes that mediate T cell identity and diversity.
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Affiliation(s)
- Mahdieh Golzari-Sorkheh
- Department of Immunology, University of Toronto & Sunnybrook Research Institute, Toronto, ON, Canada
| | - Kogulan Yoganathan
- Department of Immunology, University of Toronto & Sunnybrook Research Institute, Toronto, ON, Canada
| | - Edward L Y Chen
- Department of Immunology, University of Toronto & Sunnybrook Research Institute, Toronto, ON, Canada
| | - Jastaranpreet Singh
- Department of Immunology, University of Toronto & Sunnybrook Research Institute, Toronto, ON, Canada
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3
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Hu J, Pan M, Reid B, Tworoger S, Li B. Quantifiable blood TCR repertoire components associate with immune aging. Nat Commun 2024; 15:8171. [PMID: 39289351 PMCID: PMC11408526 DOI: 10.1038/s41467-024-52522-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2024] [Accepted: 09/11/2024] [Indexed: 09/19/2024] Open
Abstract
T cell senescence alters the homeostasis of distinct T cell populations and results in decayed adaptive immune protection in older individuals, but a link between aging and dynamic T cell clone changes has not been made. Here, using a newly developed computational framework, Repertoire Functional Units (RFU), we investigate over 6500 publicly available TCR repertoire sequencing samples from multiple human cohorts and identify age-associated RFUs consistently across different cohorts. Quantification of RFU reduction with aging reveals accelerated loss under immunosuppressive conditions. Systematic analysis of age-associated RFUs in clinical samples manifests a potential link between these RFUs and improved clinical outcomes, such as lower ICU admission and reduced risk of complications, during acute viral infections. Finally, patients receiving bone marrow transplantation show a secondary expansion of the age-associated clones upon stem cell transfer from younger donors. Together, our results suggest the existence of a 'TCR clock' that could reflect the immune functions in aging populations.
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Affiliation(s)
- Jing Hu
- Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
- Department of Pathology and Laboratory Medicine, Children's Hospital of Philadelphia, Philadelphia, PA, USA
| | - Mingyao Pan
- Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Brett Reid
- Department of Cancer Epidemiology, Moffitt Cancer Center, Tampa, FL, USA
| | - Shelley Tworoger
- Department of Cancer Epidemiology, Moffitt Cancer Center, Tampa, FL, USA
- Knight Cancer Institute and Division of Oncological Sciences, Oregon Health and Science University, Portland, OR, USA
| | - Bo Li
- Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
- Department of Pathology and Laboratory Medicine, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
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Wyatt-Johnson SK, Afify R, Brutkiewicz RR. The immune system in neurological diseases: What innate-like T cells have to say. J Allergy Clin Immunol 2024; 153:913-923. [PMID: 38365015 PMCID: PMC10999338 DOI: 10.1016/j.jaci.2024.02.003] [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: 09/18/2023] [Revised: 01/26/2024] [Accepted: 02/13/2024] [Indexed: 02/18/2024]
Abstract
The immune system classically consists of 2 lines of defense, innate and adaptive, both of which interact with one another effectively to protect us against any pathogenic threats. Importantly, there is a diverse subset of cells known as innate-like T cells that act as a bridge between the innate and adaptive immune systems and are pivotal players in eliciting inflammatory immune responses. A growing body of evidence has demonstrated the regulatory impact of these innate-like T cells in central nervous system (CNS) diseases and that such immune cells can traffic into the brain in multiple pathological conditions, which can be typically attributed to the breakdown of the blood-brain barrier. However, until now, it has been poorly understood whether innate-like T cells have direct protective or causative properties, particularly in CNS diseases. Therefore, in this review, our attention is focused on discussing the critical roles of 3 unique subsets of unconventional T cells, namely, natural killer T cells, γδ T cells, and mucosal-associated invariant T cells, in the context of CNS diseases, disorders, and injuries and how the interplay of these immune cells modulates CNS pathology, in an attempt to gain a better understanding of their complex functions.
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Affiliation(s)
- Season K Wyatt-Johnson
- Department of Microbiology and Immunology, Stark Neurosciences Research Institute, Indiana University School of Medicine, Indianapolis, Ind
| | - Reham Afify
- Department of Microbiology and Immunology, Stark Neurosciences Research Institute, Indiana University School of Medicine, Indianapolis, Ind
| | - Randy R Brutkiewicz
- Department of Microbiology and Immunology, Stark Neurosciences Research Institute, Indiana University School of Medicine, Indianapolis, Ind.
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5
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Smits HH, Jochems SP. Diverging patterns in innate immunity against respiratory viruses during a lifetime: lessons from the young and the old. Eur Respir Rev 2024; 33:230266. [PMID: 39009407 PMCID: PMC11262623 DOI: 10.1183/16000617.0266-2023] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2023] [Accepted: 04/16/2024] [Indexed: 07/17/2024] Open
Abstract
Respiratory viral infections frequently lead to severe respiratory disease, particularly in vulnerable populations such as young children, individuals with chronic lung conditions and older adults, resulting in hospitalisation and, in some cases, fatalities. The innate immune system plays a crucial role in monitoring for, and initiating responses to, viruses, maintaining a state of preparedness through the constant expression of antimicrobial defence molecules. Throughout the course of infection, innate immunity remains actively involved, contributing to viral clearance and damage control, with pivotal contributions from airway epithelial cells and resident and newly recruited immune cells. In instances where viral infections persist or are not effectively eliminated, innate immune components prominently contribute to the resulting pathophysiological consequences. Even though both young children and older adults are susceptible to severe respiratory disease caused by various respiratory viruses, the underlying mechanisms may differ significantly. Children face the challenge of developing and maturing their immunity, while older adults contend with issues such as immune senescence and inflammaging. This review aims to compare the innate immune responses in respiratory viral infections across both age groups, identifying common central hubs that could serve as promising targets for innovative therapeutic and preventive strategies, despite the apparent differences in underlying mechanisms.
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Affiliation(s)
- Hermelijn H Smits
- Leiden University Center of Infectious Disease (LU-CID), Leiden University Medical Center, Leiden, The Netherlands
| | - Simon P Jochems
- Leiden University Center of Infectious Disease (LU-CID), Leiden University Medical Center, Leiden, The Netherlands
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6
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Shrinivasan R, Wyatt-Johnson SK, Brutkiewicz RR. The MR1/MAIT cell axis in CNS diseases. Brain Behav Immun 2024; 116:321-328. [PMID: 38157945 PMCID: PMC10842441 DOI: 10.1016/j.bbi.2023.12.029] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/23/2023] [Revised: 12/14/2023] [Accepted: 12/21/2023] [Indexed: 01/03/2024] Open
Abstract
Mucosal-associated invariant T (MAIT) cells are a subpopulation of innate-like T cells that can be found throughout the body, predominantly in mucosal sites, the lungs and in the peripheral blood. MAIT cells recognize microbial-derived vitamin B (e.g., riboflavin) metabolite antigens that are presented by the major histocompatibility complex class I-like protein, MR1, found on a variety of cell types in the periphery and the CNS. Since their original discovery, MAIT cells have been studied predominantly in their roles in diseases in the periphery; however, it was not until the early 2000s that these cells were first examined for their contributions to disorders of the CNS, with the bulk of the work being done within the past few years. Currently, the MR1/MAIT cell axis has been investigated in only a few neurological diseases including, multiple sclerosis and experimental autoimmune encephalomyelitis, brain cancer/tumors, ischemia, cerebral palsy, general aging and, most recently, Alzheimer's disease. Each of these diseases demonstrates a role for this under-studied innate immune axis in its neuropathology. Together, they highlight the importance of studying the MR1/MAIT cell axis in CNS disorders. Here, we review the contributions of the MR1/MAIT cell axis in the progression or remission of these neurological diseases. This work has shed some light in terms of potentially exploiting the MR1/MAIT cell axis in novel therapeutic applications.
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Affiliation(s)
- Rashmi Shrinivasan
- Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Season K Wyatt-Johnson
- Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, IN, USA; Stark Neurosciences Research Institute, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Randy R Brutkiewicz
- Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, IN, USA; Stark Neurosciences Research Institute, Indiana University School of Medicine, Indianapolis, IN, USA.
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7
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Wu S, Yang X, Lou Y, Xiao X. MAIT cells in bacterial infectious diseases: heroes, villains, or both? Clin Exp Immunol 2023; 214:144-153. [PMID: 37624404 PMCID: PMC10714195 DOI: 10.1093/cei/uxad102] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2023] [Revised: 08/20/2023] [Accepted: 08/21/2023] [Indexed: 08/26/2023] Open
Abstract
Due to the aggravation of bacterial drug resistance and the lag in the development of new antibiotics, it is crucial to develop novel therapeutic regimens for bacterial infectious diseases. Currently, immunotherapy is a promising regimen for the treatment of infectious diseases. Mucosal-associated invariant T (MAIT) cells, a subpopulation of innate-like T cells, are abundant in humans and can mount a rapid immune response to pathogens, thus becoming a potential target of immunotherapy for infectious diseases. At the site of infection, activated MAIT cells perform complex biological functions by secreting a variety of cytokines and cytotoxic substances. Many studies have shown that MAIT cells have immunoprotective effects because they can bridge innate and adaptive immune responses, leading to bacterial clearance, tissue repair, and homeostasis maintenance. MAIT cells also participate in cytokine storm generation, tissue fibrosis, and cancer progression, indicating that they play a role in immunopathology. In this article, we review recent studies of MAIT cells, discuss their dual roles in bacterial infectious diseases and provide some promising MAIT cell-targeting strategies for the treatment of bacterial infectious diseases.
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Affiliation(s)
- Sihong Wu
- Wenzhou Key Laboratory of Sanitary Microbiology, Key Laboratory of Laboratory Medicine, Ministry of Education, School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, China
| | - Xi Yang
- Wenzhou Key Laboratory of Sanitary Microbiology, Key Laboratory of Laboratory Medicine, Ministry of Education, School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, China
| | - Yongliang Lou
- Wenzhou Key Laboratory of Sanitary Microbiology, Key Laboratory of Laboratory Medicine, Ministry of Education, School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, China
| | - Xingxing Xiao
- Wenzhou Key Laboratory of Sanitary Microbiology, Key Laboratory of Laboratory Medicine, Ministry of Education, School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, China
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Tognarelli EI, Gutiérrez-Vera C, Palacios PA, Pasten-Ferrada IA, Aguirre-Muñoz F, Cornejo DA, González PA, Carreño LJ. Natural Killer T Cell Diversity and Immunotherapy. Cancers (Basel) 2023; 15:5737. [PMID: 38136283 PMCID: PMC10742272 DOI: 10.3390/cancers15245737] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2023] [Revised: 11/28/2023] [Accepted: 12/02/2023] [Indexed: 12/24/2023] Open
Abstract
Invariant natural killer T cells (iNKTs), a type of unconventional T cells, share features with NK cells and have an invariant T cell receptor (TCR), which recognizes lipid antigens loaded on CD1d molecules, a major histocompatibility complex class I (MHC-I)-like protein. This interaction produces the secretion of a wide array of cytokines by these cells, including interferon gamma (IFN-γ) and interleukin 4 (IL-4), allowing iNKTs to link innate with adaptive responses. Interestingly, molecules that bind CD1d have been identified that enable the modulation of these cells, highlighting their potential pro-inflammatory and immunosuppressive capacities, as required in different clinical settings. In this review, we summarize key features of iNKTs and current understandings of modulatory α-galactosylceramide (α-GalCer) variants, a model iNKT cell activator that can shift the outcome of adaptive immune responses. Furthermore, we discuss advances in the development of strategies that modulate these cells to target pathologies that are considerable healthcare burdens. Finally, we recapitulate findings supporting a role for iNKTs in infectious diseases and tumor immunotherapy.
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Affiliation(s)
- Eduardo I. Tognarelli
- Millennium Institute on Immunology and Immunotherapy, Santiago 8330025, Chile; (E.I.T.); (C.G.-V.); (P.A.P.); (I.A.P.-F.); (F.A.-M.); (D.A.C.)
- Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago 8331150, Chile
| | - Cristián Gutiérrez-Vera
- Millennium Institute on Immunology and Immunotherapy, Santiago 8330025, Chile; (E.I.T.); (C.G.-V.); (P.A.P.); (I.A.P.-F.); (F.A.-M.); (D.A.C.)
- Programa de Inmunología, Instituto de Ciencias Biomédicas, Facultad de Medicina, Universidad de Chile, Santiago 8380453, Chile
| | - Pablo A. Palacios
- Millennium Institute on Immunology and Immunotherapy, Santiago 8330025, Chile; (E.I.T.); (C.G.-V.); (P.A.P.); (I.A.P.-F.); (F.A.-M.); (D.A.C.)
- Programa de Inmunología, Instituto de Ciencias Biomédicas, Facultad de Medicina, Universidad de Chile, Santiago 8380453, Chile
| | - Ignacio A. Pasten-Ferrada
- Millennium Institute on Immunology and Immunotherapy, Santiago 8330025, Chile; (E.I.T.); (C.G.-V.); (P.A.P.); (I.A.P.-F.); (F.A.-M.); (D.A.C.)
- Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago 8331150, Chile
| | - Fernanda Aguirre-Muñoz
- Millennium Institute on Immunology and Immunotherapy, Santiago 8330025, Chile; (E.I.T.); (C.G.-V.); (P.A.P.); (I.A.P.-F.); (F.A.-M.); (D.A.C.)
- Programa de Inmunología, Instituto de Ciencias Biomédicas, Facultad de Medicina, Universidad de Chile, Santiago 8380453, Chile
| | - Daniel A. Cornejo
- Millennium Institute on Immunology and Immunotherapy, Santiago 8330025, Chile; (E.I.T.); (C.G.-V.); (P.A.P.); (I.A.P.-F.); (F.A.-M.); (D.A.C.)
- Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago 8331150, Chile
| | - Pablo A. González
- Millennium Institute on Immunology and Immunotherapy, Santiago 8330025, Chile; (E.I.T.); (C.G.-V.); (P.A.P.); (I.A.P.-F.); (F.A.-M.); (D.A.C.)
- Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago 8331150, Chile
| | - Leandro J. Carreño
- Millennium Institute on Immunology and Immunotherapy, Santiago 8330025, Chile; (E.I.T.); (C.G.-V.); (P.A.P.); (I.A.P.-F.); (F.A.-M.); (D.A.C.)
- Programa de Inmunología, Instituto de Ciencias Biomédicas, Facultad de Medicina, Universidad de Chile, Santiago 8380453, Chile
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9
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Wang X, Liang M, Song P, Guan W, Shen X. Mucosal-associated invariant T cells in digestive tract: Local guardians or destroyers? Immunology 2023; 170:167-179. [PMID: 37132045 DOI: 10.1111/imm.13653] [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: 12/08/2022] [Accepted: 04/17/2023] [Indexed: 05/04/2023] Open
Abstract
Mucosa-associated invariant T cells (MAIT) are a class of innate-like T lymphocytes mainly presenting CD8+ phenotype with a semi-invariant αβ T-cell receptor, which specifically recognises MR1-presented biosynthetic derivatives of riboflavin synthesis produced by various types of microbiomes. As innate-like T lymphocytes, MAIT can be activated by a variety of cytokines, leading to immediate immune responses to infection and tumour cues. As an organ that communicates with the external environment, the digestive tract, especially the gastrointestinal tract, contains abundant microbial populations. Communication between MAIT and local microbiomes is important for the homeostasis of mucosal immunity. In addition, accumulating evidence suggests changes in the abundance and structure of the microbial community during inflammation and tumorigenesis plays a critical role in disease progress partly through their impact on MAIT development and function. Therefore, it is essential for the understanding of MAIT response and their interaction with microbiomes in the digestive tract. Here, we summarised MAIT characteristics in the digestive tract and its alteration facing inflammation and tumour, raising that targeting MAIT can be a candidate for treatment of gastrointestinal diseases.
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Affiliation(s)
- Xingzhou Wang
- Department of General Surgery, Affiliated Drum Tower Hospital, Nanjing University Medical School, Nanjing, China
| | - Mengjie Liang
- Department of General Surgery, Affiliated Drum Tower Hospital, Nanjing University Medical School, Nanjing, China
| | - Peng Song
- Department of General Surgery, Affiliated Drum Tower Hospital, Nanjing University Medical School, Nanjing, China
| | - Wenxian Guan
- Department of General Surgery, Affiliated Drum Tower Hospital, Nanjing University Medical School, Nanjing, China
| | - Xiaofei Shen
- Department of General Surgery, Affiliated Drum Tower Hospital, Nanjing University Medical School, Nanjing, China
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10
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Dikiy S, Rudensky AY. Principles of regulatory T cell function. Immunity 2023; 56:240-255. [PMID: 36792571 DOI: 10.1016/j.immuni.2023.01.004] [Citation(s) in RCA: 140] [Impact Index Per Article: 70.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2022] [Revised: 01/06/2023] [Accepted: 01/09/2023] [Indexed: 02/16/2023]
Abstract
Regulatory T (Treg) cells represent a distinct lineage of cells of the adaptive immune system indispensable for forestalling fatal autoimmune and inflammatory pathologies. The role of Treg cells as principal guardians of the immune system can be attributed to their ability to restrain all currently recognized major types of inflammatory responses through modulating the activity of a wide range of cells of the innate and adaptive immune system. This broad purview over immunity and inflammation is afforded by the multiple modes of action Treg cells exert upon their diverse molecular and cellular targets. Beyond the suppression of autoimmunity for which they were originally recognized, Treg cells have been implicated in tissue maintenance, repair, and regeneration under physiologic and pathologic conditions. Herein, we discuss the current and emerging understanding of Treg cell effector mechanisms in the context of the basic properties of Treg cells that endow them with such functional versatility.
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Affiliation(s)
- Stanislav Dikiy
- Howard Hughes Medical Institute and Immunology Program, Sloan Kettering Institute, Ludwig Center at Memorial Sloan Kettering Cancer Center, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Immunology and Microbial Pathogenesis Program, Weill Cornell Graduate School of Medical Sciences, New York, NY 10021, USA.
| | - Alexander Y Rudensky
- Howard Hughes Medical Institute and Immunology Program, Sloan Kettering Institute, Ludwig Center at Memorial Sloan Kettering Cancer Center, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
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11
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Kim OS, Park KJ, Jin HM, Cho YN, Kim YS, Kwon SH, Koh JT, Ju JK, Kee SJ, Park YW. Activation and increased production of interleukin-17 and tumour necrosis factor-α of mucosal-associated invariant T cells in patients with periodontitis. J Clin Periodontol 2022; 49:706-716. [PMID: 35569027 DOI: 10.1111/jcpe.13648] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2021] [Revised: 04/08/2022] [Accepted: 05/10/2022] [Indexed: 12/28/2022]
Abstract
AIM Mucosal-associated invariant T (MAIT) cells are known to be resident in oral mucosal tissue, but their roles in periodontitis are unknown. This study aimed to examine the level and function of MAIT cells in periodontitis patients. MATERIALS AND METHODS Frequency, activation, and function of MAIT cells from 28 periodontitis patients and 28 healthy controls (HCs) were measured by flow cytometry. RESULTS Circulating MAIT cells were numerically reduced in periodontitis patients. Moreover, they exhibited higher expression of CD69 and annexin V, together with more increased production of interleukin (IL)-17 and tumour necrosis factor (TNF)-α, in periodontitis patients than in HCs. Interestingly, periodontitis patients had higher frequencies of MAIT cells in gingival tissue than in peripheral blood. In addition, circulating MAIT cells had elevated expression of tissue-homing chemokine receptors such as CCR6 and CXCR6, and the corresponding chemokines (i.e., CCL20 and CXCL16) were more strongly expressed in inflamed gingiva than in healthy gingiva. CONCLUSIONS This study demonstrates that circulating MAIT cells are numerically deficient with an activated profile toward the production of IL-17 and TNF-α in periodontitis patients. Furthermore, circulating MAIT cells have the potential to migrate to inflamed gingival tissues.
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Affiliation(s)
- Ok-Su Kim
- Department of Periodontology, School of Dentistry, Chonnam National University, Gwangju, Republic of Korea.,Hard-Tissue Biointerface Research Center, School of Dentistry, Chonnam National University, Gwangju, Republic of Korea
| | - Ki-Jeong Park
- Department of Rheumatology, Chonnam National University Medical School and Hospital, Gwangju, Republic of Korea
| | - Hye-Mi Jin
- Department of Rheumatology, Chonnam National University Medical School and Hospital, Gwangju, Republic of Korea
| | - Young-Nan Cho
- Department of Rheumatology, Chonnam National University Medical School and Hospital, Gwangju, Republic of Korea
| | - Ye Seul Kim
- Department of Periodontology, School of Dentistry, Chonnam National University, Gwangju, Republic of Korea
| | - Seung-Hee Kwon
- Hard-Tissue Biointerface Research Center, School of Dentistry, Chonnam National University, Gwangju, Republic of Korea.,Department of Pharmacology and Dental Therapeutics, School of Dentistry, Chonnam National University, Gwangju, Republic of Korea
| | - Jeong-Tae Koh
- Hard-Tissue Biointerface Research Center, School of Dentistry, Chonnam National University, Gwangju, Republic of Korea.,Department of Pharmacology and Dental Therapeutics, School of Dentistry, Chonnam National University, Gwangju, Republic of Korea
| | - Jae Kyun Ju
- Department of Surgery, Chonnam National University Medical School and Hospital, Gwangju, Republic of Korea
| | - Seung-Jung Kee
- Department of Laboratory Medicine, Chonnam National University Medical School and Hospital, Gwangju, Republic of Korea
| | - Yong-Wook Park
- Department of Rheumatology, Chonnam National University Medical School and Hospital, Gwangju, Republic of Korea
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12
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Naidoo K, Woods K, Pellefigues C, Cait A, O'Sullivan D, Gell K, Marshall AJ, Anderson RJ, Li Y, Schmidt A, Prasit K, Mayer JU, Gestin A, Hermans IF, Painter G, Jacobsen EA, Gasser O. MR1-dependent immune surveillance of the skin contributes to pathogenesis and is a photobiological target of UV light therapy in a mouse model of atopic dermatitis. Allergy 2021; 76:3155-3170. [PMID: 34185885 DOI: 10.1111/all.14994] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2021] [Revised: 05/09/2021] [Accepted: 05/24/2021] [Indexed: 12/16/2022]
Abstract
BACKGROUND Mucosal-associated invariant T (MAIT) cells are unconventional T cells which recognize microbial metabolites presented by the major histocompatibility complex class I-related molecule MR1. Although MAIT cells have been shown to reside in human and murine skin, their contribution to atopic dermatitis (AD), an inflammatory skin disease associated with barrier dysfunction and microbial translocation, has not yet been determined. METHODS Genetic deletion of MR1 and topical treatment with inhibitory MR1 ligands, which result in the absence and functional inhibition of MAIT cells, respectively, were used to investigate the role of MR1-dependent immune surveillance in a MC903-driven murine model of AD. RESULTS The absence or inhibition of MR1 arrested AD disease progression through the blockade of both eosinophil activation and recruitment of IL-4- and IL-13-producing cells. In addition, the therapeutic efficacy of phototherapy against MC903-driven AD could be increased with prior application of folate, which photodegrades into the inhibitory MR1 ligand 6-formylpterin. CONCLUSION We identified MAIT cells as sentinels and mediators of cutaneous type 2 immunity. Their pathogenic activity can be inhibited by topical application or endogenous generation, via phototherapy, of inhibitory MR1 ligands.
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Affiliation(s)
- Karmella Naidoo
- Malaghan Institute of Medical Research Wellington New Zealand
| | - Katherine Woods
- Malaghan Institute of Medical Research Wellington New Zealand
| | | | - Alissa Cait
- Malaghan Institute of Medical Research Wellington New Zealand
| | - David O'Sullivan
- Malaghan Institute of Medical Research Wellington New Zealand
- High‐Value Nutrition National Science Challenge Auckland New Zealand
| | - Katie Gell
- Malaghan Institute of Medical Research Wellington New Zealand
| | - Andrew J. Marshall
- Ferrier Research Institute Victoria University of Wellington Lower Hutt New Zealand
| | - Regan J. Anderson
- Ferrier Research Institute Victoria University of Wellington Lower Hutt New Zealand
| | - Yanyan Li
- Malaghan Institute of Medical Research Wellington New Zealand
- High‐Value Nutrition National Science Challenge Auckland New Zealand
| | - Alfonso Schmidt
- Malaghan Institute of Medical Research Wellington New Zealand
| | - Kef Prasit
- Malaghan Institute of Medical Research Wellington New Zealand
| | | | - Aurelie Gestin
- Malaghan Institute of Medical Research Wellington New Zealand
| | - Ian F. Hermans
- Malaghan Institute of Medical Research Wellington New Zealand
| | - Gavin Painter
- Ferrier Research Institute Victoria University of Wellington Lower Hutt New Zealand
| | - Elizabeth A. Jacobsen
- Division of Allergy, Asthma and Clinical Immunology Mayo Clinic Arizona Scottsdale AZ USA
| | - Olivier Gasser
- Malaghan Institute of Medical Research Wellington New Zealand
- High‐Value Nutrition National Science Challenge Auckland New Zealand
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13
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Yasutomi Y, Chiba A, Haga K, Murayama G, Makiyama A, Kuga T, Watanabe M, Okamoto R, Nagahara A, Nagaishi T, Miyake S. Activated Mucosal-associated Invariant T Cells Have a Pathogenic Role in a Murine Model of Inflammatory Bowel Disease. Cell Mol Gastroenterol Hepatol 2021; 13:81-93. [PMID: 34461283 PMCID: PMC8593615 DOI: 10.1016/j.jcmgh.2021.08.018] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/23/2020] [Revised: 08/20/2021] [Accepted: 08/20/2021] [Indexed: 12/13/2022]
Abstract
BACKGROUND & AIMS Mucosal-associated invariant T (MAIT) cells are innate-like T cells restricted by major histocompatibility complex-related molecule 1 (MR1) and express a semi-invariant T cell receptor. Previously, we reported the activation status of circulating MAIT cells in patients with ulcerative colitis (UC) was associated with disease activity and that these cells had infiltrated the inflamed colonic mucosa. These findings suggest MAIT cells are involved in the pathogenesis of inflammatory bowel disease. We investigated the role of MAIT cells in the pathogenesis of colitis by using MR1-/- mice lacking MAIT cells and a synthetic antagonistic MR1 ligand. METHODS Oxazolone colitis was induced in MR1-/- mice (C57BL/6 background), their littermate wild-type controls, and C57BL/6 mice orally administered an antagonistic MR1 ligand, isobutyl 6-formyl pterin (i6-FP). Cytokine production of splenocytes and colonic lamina propria lymphocytes from mice receiving i6-FP was analyzed. Intestinal permeability was assessed in MR1-/- and i6-FP-treated mice and their controls. The effect of i6-FP on cytokine production by MAIT cells from patients with UC was assessed. RESULTS MR1 deficiency or i6-FP treatment reduced the severity of oxazolone colitis. i6-FP treatment reduced cytokine production in MAIT cells from mice and patients with UC. Although MR1 deficiency increased the intestinal permeability, i6-FP administration did not affect gut integrity in mice. CONCLUSIONS These results indicate MAIT cells have a pathogenic role in colitis and suppression of MAIT cell activation might reduce the severity of colitis without affecting gut integrity. Thus, MAIT cells are potential therapeutic targets for inflammatory bowel disease including UC.
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Affiliation(s)
- Yusuke Yasutomi
- Department of Immunology, Juntendo University Graduate School of Medicine, Tokyo, Japan
| | - Asako Chiba
- Department of Immunology, Juntendo University Graduate School of Medicine, Tokyo, Japan,Correspondence Address correspondence to: Asako Chiba, MD, PhD and Sachiko Miyake, MD, PhD, Department of Immunology, Juntendo University Graduate School of Medicine, Tokyo, Japan. tel: +81-3-5812-1045; fax: +81-3-3813-0421.
| | - Keiichi Haga
- Department of Immunology, Juntendo University Graduate School of Medicine, Tokyo, Japan,Department of Gastroenterology, Juntendo University Graduate School of Medicine, Tokyo, Japan
| | - Goh Murayama
- Department of Immunology, Juntendo University Graduate School of Medicine, Tokyo, Japan,Department of Internal Medicine and Rheumatology, Juntendo University Graduate School of Medicine, Tokyo, Japan
| | - Ayako Makiyama
- Department of Immunology, Juntendo University Graduate School of Medicine, Tokyo, Japan,Department of Internal Medicine and Rheumatology, Juntendo University Graduate School of Medicine, Tokyo, Japan
| | - Taiga Kuga
- Department of Immunology, Juntendo University Graduate School of Medicine, Tokyo, Japan,Department of Internal Medicine and Rheumatology, Juntendo University Graduate School of Medicine, Tokyo, Japan
| | - Mamoru Watanabe
- Advanced Research Institute, Tokyo Medical and Dental University, Tokyo, Japan
| | - Ryuichi Okamoto
- Department of Gastroenterology, Graduate School of Medical Science, Tokyo Medical and Dental University, Tokyo, Japan
| | - Akihito Nagahara
- Department of Gastroenterology, Juntendo University Graduate School of Medicine, Tokyo, Japan
| | - Takashi Nagaishi
- Department of Gastroenterology, Graduate School of Medical Science, Tokyo Medical and Dental University, Tokyo, Japan
| | - Sachiko Miyake
- Department of Immunology, Juntendo University Graduate School of Medicine, Tokyo, Japan,Correspondence Address correspondence to: Asako Chiba, MD, PhD and Sachiko Miyake, MD, PhD, Department of Immunology, Juntendo University Graduate School of Medicine, Tokyo, Japan. tel: +81-3-5812-1045; fax: +81-3-3813-0421.
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14
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AlSaieedi A, Salhi A, Tifratene F, Raies AB, Hungler A, Uludag M, Van Neste C, Bajic VB, Gojobori T, Essack M. DES-Tcell is a knowledgebase for exploring immunology-related literature. Sci Rep 2021; 11:14344. [PMID: 34253812 PMCID: PMC8275784 DOI: 10.1038/s41598-021-93809-1] [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: 02/08/2021] [Accepted: 06/24/2021] [Indexed: 12/02/2022] Open
Abstract
T-cells are a subtype of white blood cells circulating throughout the body, searching for infected and abnormal cells. They have multifaceted functions that include scanning for and directly killing cells infected with intracellular pathogens, eradicating abnormal cells, orchestrating immune response by activating and helping other immune cells, memorizing encountered pathogens, and providing long-lasting protection upon recurrent infections. However, T-cells are also involved in immune responses that result in organ transplant rejection, autoimmune diseases, and some allergic diseases. To support T-cell research, we developed the DES-Tcell knowledgebase (KB). This KB incorporates text- and data-mined information that can expedite retrieval and exploration of T-cell relevant information from the large volume of published T-cell-related research. This KB enables exploration of data through concepts from 15 topic-specific dictionaries, including immunology-related genes, mutations, pathogens, and pathways. We developed three case studies using DES-Tcell, one of which validates effective retrieval of known associations by DES-Tcell. The second and third case studies focuses on concepts that are common to Grave’s disease (GD) and Hashimoto’s thyroiditis (HT). Several reports have shown that up to 20% of GD patients treated with antithyroid medication develop HT, thus suggesting a possible conversion or shift from GD to HT disease. DES-Tcell found miR-4442 links to both GD and HT, and that miR-4442 possibly targets the autoimmune disease risk factor CD6, which provides potential new knowledge derived through the use of DES-Tcell. According to our understanding, DES-Tcell is the first KB dedicated to exploring T-cell-relevant information via literature-mining, data-mining, and topic-specific dictionaries.
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Affiliation(s)
- Ahdab AlSaieedi
- Department of Medical Laboratory Technology (MLT), Faculty of Applied Medical Sciences (FAMS), King Abdulaziz University (KAU), Jeddah, 21589-80324, Saudi Arabia
| | - Adil Salhi
- Computer, Electrical, and Mathematical Sciences and Engineering Division (CEMSE), Computational Bioscience Research Center (CBRC), King Abdullah University of Science and Technology (KAUST), Thuwal, 23955-6900, Saudi Arabia
| | - Faroug Tifratene
- Computer, Electrical, and Mathematical Sciences and Engineering Division (CEMSE), Computational Bioscience Research Center (CBRC), King Abdullah University of Science and Technology (KAUST), Thuwal, 23955-6900, Saudi Arabia
| | - Arwa Bin Raies
- Computer, Electrical, and Mathematical Sciences and Engineering Division (CEMSE), Computational Bioscience Research Center (CBRC), King Abdullah University of Science and Technology (KAUST), Thuwal, 23955-6900, Saudi Arabia
| | - Arnaud Hungler
- Computer, Electrical, and Mathematical Sciences and Engineering Division (CEMSE), Computational Bioscience Research Center (CBRC), King Abdullah University of Science and Technology (KAUST), Thuwal, 23955-6900, Saudi Arabia
| | - Mahmut Uludag
- Computer, Electrical, and Mathematical Sciences and Engineering Division (CEMSE), Computational Bioscience Research Center (CBRC), King Abdullah University of Science and Technology (KAUST), Thuwal, 23955-6900, Saudi Arabia
| | - Christophe Van Neste
- Computer, Electrical, and Mathematical Sciences and Engineering Division (CEMSE), Computational Bioscience Research Center (CBRC), King Abdullah University of Science and Technology (KAUST), Thuwal, 23955-6900, Saudi Arabia
| | - Vladimir B Bajic
- Computer, Electrical, and Mathematical Sciences and Engineering Division (CEMSE), Computational Bioscience Research Center (CBRC), King Abdullah University of Science and Technology (KAUST), Thuwal, 23955-6900, Saudi Arabia
| | - Takashi Gojobori
- Computer, Electrical, and Mathematical Sciences and Engineering Division (CEMSE), Computational Bioscience Research Center (CBRC), King Abdullah University of Science and Technology (KAUST), Thuwal, 23955-6900, Saudi Arabia
| | - Magbubah Essack
- Computer, Electrical, and Mathematical Sciences and Engineering Division (CEMSE), Computational Bioscience Research Center (CBRC), King Abdullah University of Science and Technology (KAUST), Thuwal, 23955-6900, Saudi Arabia.
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15
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Hanson ED, Bates LC, Bartlett DB, Campbell JP. Does exercise attenuate age- and disease-associated dysfunction in unconventional T cells? Shining a light on overlooked cells in exercise immunology. Eur J Appl Physiol 2021; 121:1815-1834. [PMID: 33822261 DOI: 10.1007/s00421-021-04679-4] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2020] [Accepted: 03/28/2021] [Indexed: 02/06/2023]
Abstract
Unconventional T Cells (UTCs) are a unique population of immune cells that links innate and adaptive immunity. Following activation, UTCs contribute to a host of immunological activities, rapidly responding to microbial and viral infections and playing key roles in tumor suppression. Aging and chronic disease both have been shown to adversely affect UTC numbers and function, with increased inflammation, change in body composition, and physical inactivity potentially contributing to the decline. One possibility to augment circulating UTCs is through increased physical activity. Acute exercise is a potent stimulus leading to the mobilization of immune cells while the benefits of exercise training may include anti-inflammatory effects, reductions in fat mass, and improved fitness. We provide an overview of age-related changes in UTCs, along with chronic diseases that are associated with altered UTC number and function. We summarize how UTCs respond to acute exercise and exercise training and discuss potential mechanisms that may lead to improved frequency and function.
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Affiliation(s)
- Erik D Hanson
- Department of Exercise and Sport Science, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27517, USA. .,Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA. .,Human Movement Science Curriculum, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
| | - Lauren C Bates
- Department of Exercise and Sport Science, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27517, USA.,Human Movement Science Curriculum, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - David B Bartlett
- Division of Medical Oncology, Duke Cancer Institute, Duke University, Durham, NC, USA
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16
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Autophagy-Mediated Activation of Mucosal-Associated Invariant T Cells Driven by Mesenchymal Stem Cell-Derived IL-15. Stem Cell Reports 2021; 16:926-939. [PMID: 33798448 PMCID: PMC8072065 DOI: 10.1016/j.stemcr.2021.03.005] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2020] [Revised: 03/02/2021] [Accepted: 03/03/2021] [Indexed: 12/30/2022] Open
Abstract
Mucosal-associated invariant T (MAIT) cells are innate-like unconventional T cells that are abundant in humans and have attracted increasing attention in recent years. Mesenchymal stem cells (MSCs) are crucial regulators of immune cells. However, whether MAIT cells are regulated by MSCs is unclear. Here, we explored the effect of MSCs on MAIT cells and revealed the underlying mechanism. We found that MSCs did not influence the proliferation of MAIT cells but strikingly induced an activated phenotype with an increased expression of CD69, TNF-α, IFN-γ, and granzyme B. Moreover, MSCs activated MAIT cells in a TCR-MR1-independent mechanism through MSC-secreted IL-15. We revealed that MSC-derived IL-15 activated MAIT cells by enhancing autophagy activity, which was abolished by the autophagy inhibitor 3-methyladenine. Based on our findings, MAIT cells are activated by MSCs through IL-15-induced autophagy, which may help elucidate the mechanisms underlying some immune responses and diseases and provide guidance for future research.
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17
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Tao H, Pan Y, Chu S, Li L, Xie J, Wang P, Zhang S, Reddy S, Sleasman JW, Zhong XP. Differential controls of MAIT cell effector polarization by mTORC1/mTORC2 via integrating cytokine and costimulatory signals. Nat Commun 2021; 12:2029. [PMID: 33795689 PMCID: PMC8016978 DOI: 10.1038/s41467-021-22162-8] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2019] [Accepted: 03/03/2021] [Indexed: 12/27/2022] Open
Abstract
Mucosal-associated invariant T (MAIT) cells have important functions in immune responses against pathogens and in diseases, but mechanisms controlling MAIT cell development and effector lineage differentiation remain unclear. Here, we report that IL-2/IL-15 receptor β chain and inducible costimulatory (ICOS) not only serve as lineage-specific markers for IFN-γ-producing MAIT1 and IL-17A-producing MAIT17 cells, but are also important for their differentiation, respectively. Both IL-2 and IL-15 induce mTOR activation, T-bet upregulation, and subsequent MAIT cell, especially MAIT1 cell, expansion. By contrast, IL-1β induces more MAIT17 than MAIT1 cells, while IL-23 alone promotes MAIT17 cell proliferation and survival, but synergizes with IL-1β to induce strong MAIT17 cell expansion in an mTOR-dependent manner. Moreover, mTOR is dispensable for early MAIT cell development, yet pivotal for MAIT cell effector differentiation. Our results thus show that mTORC2 integrates signals from ICOS and IL-1βR/IL-23R to exert a crucial role for MAIT17 differentiation, while the IL-2/IL-15R-mTORC1-T-bet axis ensures MAIT1 differentiation.
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Affiliation(s)
- Huishan Tao
- Department of Pediatrics-Allergy and Immunology, Duke University Medical Center, Durham, NC, USA
| | - Yun Pan
- Department of Pediatrics-Allergy and Immunology, Duke University Medical Center, Durham, NC, USA
| | - Shuai Chu
- Department of Pediatrics-Allergy and Immunology, Duke University Medical Center, Durham, NC, USA
| | - Lei Li
- Department of Pediatrics-Allergy and Immunology, Duke University Medical Center, Durham, NC, USA
| | - Jinhai Xie
- Department of Pediatrics-Allergy and Immunology, Duke University Medical Center, Durham, NC, USA
| | - Peng Wang
- Department of Pediatrics-Allergy and Immunology, Duke University Medical Center, Durham, NC, USA
| | - Shimeng Zhang
- Department of Pediatrics-Allergy and Immunology, Duke University Medical Center, Durham, NC, USA
| | - Srija Reddy
- Department of Pediatrics-Allergy and Immunology, Duke University Medical Center, Durham, NC, USA
| | - John W Sleasman
- Department of Pediatrics-Allergy and Immunology, Duke University Medical Center, Durham, NC, USA
| | - Xiao-Ping Zhong
- Department of Pediatrics-Allergy and Immunology, Duke University Medical Center, Durham, NC, USA.
- Department of Immunology, Duke University Medical Center, Durham, NC, USA.
- Hematologic Malignancies and Cellular Therapies Program, Duke Cancer Institute, Duke University Medical Center, Durham, NC, USA.
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18
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Qiu W, Kang N, Wu Y, Cai Y, Xiao L, Ge H, Zhu H. Mucosal Associated Invariant T Cells Were Activated and Polarized Toward Th17 in Chronic Obstructive Pulmonary Disease. Front Immunol 2021; 12:640455. [PMID: 33868270 PMCID: PMC8044354 DOI: 10.3389/fimmu.2021.640455] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2020] [Accepted: 03/08/2021] [Indexed: 12/30/2022] Open
Abstract
Chronic obstructive pulmonary disease (COPD) is a chronic inflammatory disease characterized by airway limitation accompanied with infiltration of inflammatory cells. Mucosal associated invariant T (MAIT) cells can recognize bacteria and play an important role in controlling host immune responses by producing cytokines. In this study, we characterized the function and the ability of MAIT cells to secrete cytokines measured by flow cytometry. In COPD patients, MAIT cells have the ability to produce more IL-17 and less IFN-γ compared to healthy individuals. We found that HLA-DR expression levels reflected the degree of inflammation and the proportion of IL-17 was significantly correlated with lung function in peripheral blood. In addition, we found that MAIT cells were highly expressed in the lung, and the increased expression of CXCR2, CXCL1 indicated that MAIT cells had the potential to migrate to inflammatory tissues. This evidence implies that MAIT cells may play a potential role in COPD immunopathology.
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Affiliation(s)
- Wenjia Qiu
- Department of Respiratory Medicine, The Affiliated Huadong Hospital of Fudan University, Shanghai, China
| | - Ning Kang
- Department of Thoracic Surgery, The Affiliated Huadong Hospital of Fudan University, Shanghai, China
| | - Yanxu Wu
- Department of Respiratory Medicine, The Affiliated Huadong Hospital of Fudan University, Shanghai, China
| | - Yongjun Cai
- Department of Pathology, The Affiliated Huadong Hospital of Fudan University, Shanghai, China
| | - Li Xiao
- Department of Pathology, The Affiliated Huadong Hospital of Fudan University, Shanghai, China
| | - Haiyan Ge
- Department of Respiratory Medicine, The Affiliated Huadong Hospital of Fudan University, Shanghai, China
| | - Huili Zhu
- Department of Respiratory Medicine, The Affiliated Huadong Hospital of Fudan University, Shanghai, China
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19
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Miccoli A, Picchietti S, Fausto AM, Scapigliati G. Evolution of immune defence responses as incremental layers among Metazoa. EUROPEAN ZOOLOGICAL JOURNAL 2021. [DOI: 10.1080/24750263.2020.1849435] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/17/2023]
Affiliation(s)
- A. Miccoli
- Department for Innovation in Biological, Agro-food and Forest Systems, University of Tuscia, Largo dell’Università Snc, Viterbo, Italy
| | - S. Picchietti
- Department for Innovation in Biological, Agro-food and Forest Systems, University of Tuscia, Largo dell’Università Snc, Viterbo, Italy
| | - A. M. Fausto
- Department for Innovation in Biological, Agro-food and Forest Systems, University of Tuscia, Largo dell’Università Snc, Viterbo, Italy
| | - G. Scapigliati
- Department for Innovation in Biological, Agro-food and Forest Systems, University of Tuscia, Largo dell’Università Snc, Viterbo, Italy
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20
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Role of Peripheral Immune Cells in Multiple Sclerosis and Experimental Autoimmune Encephalomyelitis. SCI 2021. [DOI: 10.3390/sci3010012] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
Multiple sclerosis (MS) is a chronic autoimmune disease that affects the myelination of the neurons present in the central nervous system (CNS). The exact etiology of MS development is unclear, but various environmental and genetic factors might play a role in initiating the disease. Experimental autoimmune encephalomyelitis (EAE) is a mouse model that is used to study the pathophysiology of MS disease as well as the effects of possible therapeutic agents. In addition, autoreactive immune cells trigger an inflammatory process upon the recognition of CNS antigens, which leads to destruction of the neurons. These include innate immune cells such as macrophages, dendritic cells, and natural killer cells. Additionally, the activation and extravasation of adaptive immune cells such as CD4+ T cells into the CNS may lead to further exacerbation of the disease. However, many studies revealed that immune cells could have either a protective or pathological role in MS. In this review, we highlight the roles of innate and adaptive immune cellular and soluble players that contribute to the pathogenesis of MS and EAE, which may be used as potential targets for therapy.
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21
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Zhao Y, Aldoss I, Qu C, Crawford JC, Gu Z, Allen EK, Zamora AE, Alexander TB, Wang J, Goto H, Imamura T, Akahane K, Marcucci G, Stein AS, Bhatia R, Thomas PG, Forman SJ, Mullighan CG, Roberts KG. Tumor-intrinsic and -extrinsic determinants of response to blinatumomab in adults with B-ALL. Blood 2021; 137:471-484. [PMID: 32881995 PMCID: PMC7845009 DOI: 10.1182/blood.2020006287] [Citation(s) in RCA: 86] [Impact Index Per Article: 21.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2020] [Accepted: 08/20/2020] [Indexed: 12/16/2022] Open
Abstract
Blinatumomab, a bispecific antibody that directs CD3+ T cells to CD19+ tumor cells, shows variable efficacy in B-progenitor acute lymphoblastic leukemia (B-ALL). To determine tumor-intrinsic and -extrinsic determinants of response, we studied 44 adults with relapsed or refractory B-ALL (including 2 minimal residual disease positive) treated with blinatumomab using bulk tumor and single-cell sequencing. The overall response rate in patients with hematological disease was 55%, with a high response rate in those with CRLF2-rearranged Philadelphia chromosome-like ALL (12 [75%] of 16). Pretreatment samples of responders exhibited a tumor-intrinsic transcriptomic signature of heightened immune response. Multiple mechanisms resulted in loss of CD19 expression, including CD19 mutations, CD19-mutant allele-specific expression, low CD19 RNA expression, and mutations in CD19 signaling complex member CD81. Patients with low hypodiploid ALL were prone to CD19- relapse resulting from aneuploidy-mediated loss of the nonmutated CD19 allele. Increased expression of a CD19 isoform with intraexonic splicing of exon 2, CD19 ex2part, at baseline or during therapy was associated with treatment failure. These analyses demonstrate both tumor-intrinsic and -extrinsic factors influence blinatumomab response. We show that CD19 mutations are commonly detected in CD19- relapse during blinatumomab treatment. Identification of the CD19 ex2part splice variant represents a new biomarker predictive of blinatumomab therapy failure.
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MESH Headings
- Adolescent
- Adult
- Aged
- Amino Acid Sequence
- Aneuploidy
- Antibodies, Bispecific/immunology
- Antibodies, Bispecific/pharmacology
- Antibodies, Bispecific/therapeutic use
- Antigens, CD19/biosynthesis
- Antigens, CD19/genetics
- Antigens, CD19/immunology
- Antigens, Neoplasm/biosynthesis
- Antigens, Neoplasm/genetics
- Antigens, Neoplasm/immunology
- Antineoplastic Agents, Immunological/immunology
- Antineoplastic Agents, Immunological/pharmacology
- Antineoplastic Agents, Immunological/therapeutic use
- B-Lymphocytes/drug effects
- B-Lymphocytes/immunology
- Cytotoxicity, Immunologic/drug effects
- Drug Resistance, Neoplasm/physiology
- Female
- Gene Expression Profiling
- Humans
- Male
- Middle Aged
- Mutation
- Precursor B-Cell Lymphoblastic Leukemia-Lymphoma/drug therapy
- Precursor B-Cell Lymphoblastic Leukemia-Lymphoma/genetics
- Protein Isoforms/antagonists & inhibitors
- Protein Isoforms/genetics
- RNA, Messenger/biosynthesis
- RNA, Messenger/genetics
- RNA, Neoplasm/biosynthesis
- RNA, Neoplasm/genetics
- Recurrence
- Retrospective Studies
- Salvage Therapy
- Sequence Alignment
- Sequence Homology, Amino Acid
- Single-Cell Analysis
- T-Lymphocyte Subsets/drug effects
- T-Lymphocyte Subsets/immunology
- Young Adult
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Affiliation(s)
- Yaqi Zhao
- Department of Pathology, St Jude Children's Research Hospital, Memphis, TN
| | - Ibrahim Aldoss
- Department of Hematology and Hematopoietic Cell Transplantation, Gehr Family Center for Leukemia Research, City of Hope Medical Center, Duarte, CA
| | - Chunxu Qu
- Department of Pathology, St Jude Children's Research Hospital, Memphis, TN
| | | | - Zhaohui Gu
- Department of Pathology, St Jude Children's Research Hospital, Memphis, TN
| | - Emma K Allen
- Department of Immunology, St Jude Children's Research Hospital, Memphis, TN
| | - Anthony E Zamora
- Department of Immunology, St Jude Children's Research Hospital, Memphis, TN
| | | | - Jeremy Wang
- Department of Genetics, University of North Carolina, Chapel Hill, NC
| | - Hiroaki Goto
- Division of Hemato-Oncology/Regenerative Medicine, Kanagawa Children's Medical Center, Yokohama, Japan
| | - Toshihiko Imamura
- Department of Pediatrics, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Koshi Akahane
- Department of Pediatrics, School of Medicine, University of Yamanashi, Chuo, Japan; and
| | - Guido Marcucci
- Department of Hematology and Hematopoietic Cell Transplantation, Gehr Family Center for Leukemia Research, City of Hope Medical Center, Duarte, CA
| | - Anthony S Stein
- Department of Hematology and Hematopoietic Cell Transplantation, Gehr Family Center for Leukemia Research, City of Hope Medical Center, Duarte, CA
| | - Ravi Bhatia
- Division of Hematology and Oncology, University of Alabama at Birmingham, Birmingham, AL
| | - Paul G Thomas
- Department of Immunology, St Jude Children's Research Hospital, Memphis, TN
| | - Stephen J Forman
- Department of Hematology and Hematopoietic Cell Transplantation, Gehr Family Center for Leukemia Research, City of Hope Medical Center, Duarte, CA
| | | | - Kathryn G Roberts
- Department of Pathology, St Jude Children's Research Hospital, Memphis, TN
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22
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Cho YN, Jeong HS, Park KJ, Kim HS, Kim EH, Jin HM, Jung HJ, Ju JK, Choi SE, Kang JH, Park DJ, Kim TJ, Lee SS, Kee SJ, Park YW. Altered distribution and enhanced osteoclastogenesis of mucosal-associated invariant T cells in gouty arthritis. Rheumatology (Oxford) 2021; 59:2124-2134. [PMID: 32087015 DOI: 10.1093/rheumatology/keaa020] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2019] [Revised: 01/08/2020] [Indexed: 12/27/2022] Open
Abstract
OBJECTIVE This study was designed to investigate the role of mucosal-associated invariant T (MAIT) cells in gouty arthritis (GA) and their effects on osteoclastogenesis. METHODS Patients with GA (n = 61), subjects with hyperuricaemia (n = 11) and healthy controls (n = 30) were enrolled in this study. MAIT cells, cytokines, CD69, programmed death-1 (PD-1) and lymphocyte-activation gene 3 (LAG-3) levels were measured by flow cytometry. In vitro osteoclastogenesis experiments were performed using peripheral blood mononuclear cells in the presence of M-CSF and RANK ligand. RESULTS Circulating MAIT cell levels were significantly reduced in GA patients. However, their capacities for IFN-γ, IL-17 and TNF-α production were preserved. Expression levels of CD69, PD-1 and LAG-3 in MAIT cells were found to be elevated in GA patients. In particular, CD69 expression in circulating MAIT cells was increased by stimulation with MSU crystals, suggesting that deposition of MSU crystals might contribute to MAIT cell activation. Interestingly, MAIT cells were found to be accumulated in synovial fluid and infiltrated into gouty tophus tissues within joints. Furthermore, activated MAIT cells secreted pro-resorptive cytokines (i.e. IL-6, IL-17 and TNF-α) and facilitated osteoclastogenesis. CONCLUSION This study demonstrates that circulating MAIT cells are activated and numerically deficient in GA patients. In addition, MAIT cells have the potential to migrate to inflamed tissues and induce osteoclastogenesis. These findings provide an important role of MAIT cells in the pathogenesis of inflammation and bone destruction in GA patients.
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Affiliation(s)
- Young-Nan Cho
- Department of RheumatologyChonnam National University Medical School and Hospital, Gwangju, Republic of Korea
| | - Hae-Seong Jeong
- Department of RheumatologyChonnam National University Medical School and Hospital, Gwangju, Republic of Korea
| | - Ki-Jeong Park
- Department of RheumatologyChonnam National University Medical School and Hospital, Gwangju, Republic of Korea
| | - Hyung-Seok Kim
- Department of Forensic MedicineChonnam National University Medical School and Hospital, Gwangju, Republic of Korea
| | - Eun-Hee Kim
- Department of Forensic MedicineChonnam National University Medical School and Hospital, Gwangju, Republic of Korea
| | - Hye-Mi Jin
- Department of RheumatologyChonnam National University Medical School and Hospital, Gwangju, Republic of Korea
| | - Hyun-Ju Jung
- Department of RheumatologyChonnam National University Medical School and Hospital, Gwangju, Republic of Korea
| | - Jae Kyun Ju
- Department of Surgery, Chonnam National University Medical School and Hospital, Gwangju, Republic of Korea
| | - Sung-Eun Choi
- Department of RheumatologyChonnam National University Medical School and Hospital, Gwangju, Republic of Korea
| | - Ji-Hyoun Kang
- Department of RheumatologyChonnam National University Medical School and Hospital, Gwangju, Republic of Korea
| | - Dong-Jin Park
- Department of RheumatologyChonnam National University Medical School and Hospital, Gwangju, Republic of Korea
| | - Tae-Jong Kim
- Department of RheumatologyChonnam National University Medical School and Hospital, Gwangju, Republic of Korea
| | - Shin-Seok Lee
- Department of RheumatologyChonnam National University Medical School and Hospital, Gwangju, Republic of Korea
| | - Seung-Jung Kee
- Department of Laboratory Medicine, Chonnam National University Medical School and Hospital, Gwangju, Republic of Korea
| | - Yong-Wook Park
- Department of RheumatologyChonnam National University Medical School and Hospital, Gwangju, Republic of Korea
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23
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Rosine N, Miceli-Richard C. Innate Cells: The Alternative Source of IL-17 in Axial and Peripheral Spondyloarthritis? Front Immunol 2021; 11:553742. [PMID: 33488572 PMCID: PMC7821711 DOI: 10.3389/fimmu.2020.553742] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2020] [Accepted: 11/09/2020] [Indexed: 12/11/2022] Open
Abstract
Spondyloarthritis (SpA) is a chronic inflammatory rheumatism characterized by inflammation of sacroiliac joints, peripheral joints, and spine. The Assessment of SpondyloArthritis Society describes three disease forms: axial (axSpA), peripheral, and enthesitic SpA. Each may be associated with extra-articular manifestations: psoriasis, inflammatory bowel disease, and acute anterior uveitis. Genome-wide association studies performed in axSpA and psoriatic arthritis (PsA) have shown a shared genetic background, especially the interleukin 23 (IL-23)/IL-17 pathway, which suggests pathophysiological similarities. The convincing positive results of clinical trials assessing the effect of secukinumab and ixekizumab (anti-IL-17A monoclonal antibodies) in axSpA and PsA have reinforced the speculated crucial role of IL-17 in SpA. Nevertheless, and obviously unexpectedly, the differential efficacy of anti-IL-23–targeted treatments between axSpA (failure) and PsA (success) has profoundly disrupted our presumed knowledge of disease pathogeny. The cells able to secrete IL-17, their dependence on IL-23, and their respective role according to the clinical form of the disease is at the heart of the current debate to potentially explain these observed differences in efficacy of IL-23/IL-17–targeted therapy. In fact, IL-17 secretion is usually mainly related to T helper 17 lymphocytes. Nevertheless, several innate immune cells express IL-23 receptor and can produce IL-17. To what extent these alternative cell populations can produce IL-17 independent of IL-23 and their respective involvement in axSpA and PsA are the crucial scientific questions in SpA. From this viewpoint, this is a nice example of a reverse path from bedside to bench, in which the results of therapeutic trials allow for reflecting more in depth on the pathophysiology of a disease. Here we provide an overview of each innate immunity-producing IL-17 cell subset and their respective role in disease pathogeny at the current level of our knowledge.
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Affiliation(s)
- Nicolas Rosine
- Unité Mixte AP-HP/Institut Pasteur, Institut Pasteur, Immunoregulation Unit, Paris, France
| | - Corinne Miceli-Richard
- Unité Mixte AP-HP/Institut Pasteur, Institut Pasteur, Immunoregulation Unit, Paris, France.,Paris University, Department of Rheumatology-Hôpital Cochin. Assistance Publique-Hôpitaux de Paris, EULAR Center of Excellence, Paris, France
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24
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Gu BH, Kim M, Yun CH. Regulation of Gastrointestinal Immunity by Metabolites. Nutrients 2021; 13:nu13010167. [PMID: 33430497 PMCID: PMC7826526 DOI: 10.3390/nu13010167] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2020] [Revised: 01/01/2021] [Accepted: 01/04/2021] [Indexed: 12/11/2022] Open
Abstract
The gastrointestinal tract contains multiple types of immune cells that maintain the balance between tolerance and activation at the first line of host defense facing non-self antigens, including dietary antigens, commensal bacteria, and sometimes unexpected pathogens. The maintenance of homeostasis at the gastrointestinal tract requires stringent regulation of immune responses against various environmental conditions. Dietary components can be converted into gut metabolites with unique functional activities through host as well as microbial enzymatic activities. Accumulating evidence demonstrates that gastrointestinal metabolites have significant impacts on the regulation of intestinal immunity and are further integrated into the immune response of distal mucosal tissue. Metabolites, especially those derived from the microbiota, regulate immune cell functions in various ways, including the recognition and activation of cell surface receptors, the control of gene expression by epigenetic regulation, and the integration of cellular metabolism. These mucosal immune regulations are key to understanding the mechanisms underlying the development of gastrointestinal disorders. Here, we review recent advancements in our understanding of the role of gut metabolites in the regulation of gastrointestinal immunity, highlighting the cellular and molecular regulatory mechanisms by macronutrient-derived metabolites.
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Affiliation(s)
- Bon-Hee Gu
- Life and Industry Convergence Research Institute, Pusan National University, Miryang 50463, Korea;
| | - Myunghoo Kim
- Life and Industry Convergence Research Institute, Pusan National University, Miryang 50463, Korea;
- Department of Animal Science, College of Natural Resources & Life Science, Pusan National University, Miryang 50463, Korea
- Correspondence: (M.K.); (C.-H.Y.)
| | - Cheol-Heui Yun
- Department of Agricultural Biotechnology and Research Institute of Agriculture and Life Sciences, Seoul National University, Seoul 08826, Korea
- Center for Food and Bioconvergence, Seoul National University, Seoul 08826, Korea
- Institute of Green-Bio Science and Technology, Seoul National University, Pyeongchang-gun, Gangwon-do 25354, Korea
- Correspondence: (M.K.); (C.-H.Y.)
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25
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De Libero G, Chancellor A, Mori L. Antigen specificities and functional properties of MR1-restricted T cells. Mol Immunol 2020; 130:148-153. [PMID: 33358568 DOI: 10.1016/j.molimm.2020.12.016] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2020] [Accepted: 12/07/2020] [Indexed: 11/25/2022]
Abstract
MR1 is an MHC class I-like molecule with unique structural and biological features that make it an important member among the molecules involved in antigen presentation to T cells. Distinctive features include ubiquitous expression of the MR1 gene and its monomorphism. Another relevant property is that the MR1 protein appears at very low levels on the plasma membrane and its surface expression is regulated by antigen binding. Finally, the nature of presented antigens differs from those that bind other presenting molecules and includes small metabolites of microbial and self-origin, small drugs and tumor-associated antigens. This opinion paper describes in detail some of those features and discusses recent literature in the field.
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26
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Liu J, Nan H, Brutkiewicz RR, Casasnovas J, Kua KL. Sex discrepancy in the reduction of mucosal-associated invariant T cells caused by obesity. IMMUNITY INFLAMMATION AND DISEASE 2020; 9:299-309. [PMID: 33332759 PMCID: PMC7860596 DOI: 10.1002/iid3.393] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/07/2020] [Revised: 11/02/2020] [Accepted: 11/28/2020] [Indexed: 01/07/2023]
Abstract
Introduction Gut microbiota has been reported to contribute to obesity and the pathology of obesity‐related diseases but the underlying mechanisms are largely unknown. Mucosal‐associated invariant T (MAIT) cells are a unique subpopulation of T cells characterized by the expression of a semi‐invariant T cell receptor (TCR) α chain (Vα19 in mice; Vα7.2 in humans). The expansion and maturation of MAIT cells require the gut microbiota and antigen‐presenting molecule MR1, suggesting that MAIT cells may play a unique role in bridging gut microbiota, obesity, and obesity‐associated inflammation. Methods The levels of human MAIT cells from obese patients, as well as mouse MAIT cells from obese mouse models, were determined by flow cytometry. By comparing to controls, we analyzed the change of MAIT cells in obese subjects. Results We found obese patients had fewer circulating MAIT cells than healthy‐weight donors and the difference was more distinct in male patients. Consistently, male mice (but not female mice) have shown reduced MAIT cells in the liver and adipose tissue after a 10‐week Western diet compared to mice on a control diet. We also explored the possibility of utilizing high‐throughput technology (i.e., quantitative polymerase chain reaction [qPCR]), other than flow cytometry, to determine the expression levels of the invariant TCR of human MAIT cells. But a minimal correlation (R2 = 0.23, p = .11) was observed between qPCR and flow cytometry data. Conclusion Our study suggests that there is a sex discrepancy in the impact of obesity on MAIT cells: MAIT cells in male (but not female) humans and male mice are reduced by obesity.
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Affiliation(s)
- Jianyun Liu
- Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, Indiana, USA
| | - Hongmei Nan
- Department of Global Health, Richard M. Fairbanks School of Public Health, Indiana University, Indianapolis, Indiana, USA.,Indiana University Melvin and Bren Simon Cancer Center, Indiana University, Indianapolis, Indiana, USA
| | - Randy R Brutkiewicz
- Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, Indiana, USA
| | - Jose Casasnovas
- Department of Pediatrics, Indiana University School of Medicine, Indianapolis, Indiana, USA
| | - Kok Lim Kua
- Department of Pediatrics, Indiana University School of Medicine, Indianapolis, Indiana, USA
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27
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Wang H, Kjer-Nielsen L, Shi M, D'Souza C, Pediongco TJ, Cao H, Kostenko L, Lim XY, Eckle SBG, Meehan BS, Zhu T, Wang B, Zhao Z, Mak JYW, Fairlie DP, Teng MWL, Rossjohn J, Yu D, de St Groth BF, Lovrecz G, Lu L, McCluskey J, Strugnell RA, Corbett AJ, Chen Z. IL-23 costimulates antigen-specific MAIT cell activation and enables vaccination against bacterial infection. Sci Immunol 2020; 4:4/41/eaaw0402. [PMID: 31732518 DOI: 10.1126/sciimmunol.aaw0402] [Citation(s) in RCA: 71] [Impact Index Per Article: 14.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2018] [Revised: 05/09/2019] [Accepted: 10/18/2019] [Indexed: 12/11/2022]
Abstract
Mucosal-associated invariant T (MAIT) cells are activated in a TCR-dependent manner by antigens derived from the riboflavin synthesis pathway, including 5-(2-oxopropylideneamino)-6-d-ribitylaminouracil (5-OP-RU), bound to MHC-related protein-1 (MR1). However, MAIT cell activation in vivo has not been studied in detail. Here, we have found and characterized additional molecular signals required for optimal activation and expansion of MAIT cells after pulmonary Legionella or Salmonella infection in mice. We show that either bone marrow-derived APCs or non-bone marrow-derived cells can activate MAIT cells in vivo, depending on the pathogen. Optimal MAIT cell activation in vivo requires signaling through the inducible T cell costimulator (ICOS), which is highly expressed on MAIT cells. Subsequent expansion and maintenance of MAIT-17/1-type responses are dependent on IL-23. Vaccination with IL-23 plus 5-OP-RU augments MAIT cell-mediated control of pulmonary Legionella infection. These findings reveal cellular and molecular targets for manipulating MAIT cell function under physiological conditions.
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Affiliation(s)
- Huimeng Wang
- Department of Microbiology and Immunology, University of Melbourne, Peter Doherty Institute for Infection and Immunity, Melbourne, VIC 3000, Australia.,State Key Laboratory of Respiratory Disease, Guangzhou Institute of Respiratory Disease, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong 510182, China
| | - Lars Kjer-Nielsen
- Department of Microbiology and Immunology, University of Melbourne, Peter Doherty Institute for Infection and Immunity, Melbourne, VIC 3000, Australia
| | - Mai Shi
- Department of Microbiology and Immunology, University of Melbourne, Peter Doherty Institute for Infection and Immunity, Melbourne, VIC 3000, Australia.,School of Medicine, Tsinghua University, Beijing, China
| | - Criselle D'Souza
- Department of Microbiology and Immunology, University of Melbourne, Peter Doherty Institute for Infection and Immunity, Melbourne, VIC 3000, Australia.,Sir Peter MacCallum Department of Oncology, University of Melbourne, VIC 3010, Australia
| | - Troi J Pediongco
- Department of Microbiology and Immunology, University of Melbourne, Peter Doherty Institute for Infection and Immunity, Melbourne, VIC 3000, Australia
| | - Hanwei Cao
- Department of Microbiology and Immunology, University of Melbourne, Peter Doherty Institute for Infection and Immunity, Melbourne, VIC 3000, Australia
| | - Lyudmila Kostenko
- Department of Microbiology and Immunology, University of Melbourne, Peter Doherty Institute for Infection and Immunity, Melbourne, VIC 3000, Australia
| | - Xin Yi Lim
- Department of Microbiology and Immunology, University of Melbourne, Peter Doherty Institute for Infection and Immunity, Melbourne, VIC 3000, Australia
| | - Sidonia B G Eckle
- Department of Microbiology and Immunology, University of Melbourne, Peter Doherty Institute for Infection and Immunity, Melbourne, VIC 3000, Australia
| | - Bronwyn S Meehan
- Department of Microbiology and Immunology, University of Melbourne, Peter Doherty Institute for Infection and Immunity, Melbourne, VIC 3000, Australia
| | - Tianyuan Zhu
- Department of Microbiology and Immunology, University of Melbourne, Peter Doherty Institute for Infection and Immunity, Melbourne, VIC 3000, Australia.,School of Medicine, Tsinghua University, Beijing, China
| | - Bingjie Wang
- Department of Microbiology and Immunology, University of Melbourne, Peter Doherty Institute for Infection and Immunity, Melbourne, VIC 3000, Australia
| | - Zhe Zhao
- Department of Microbiology and Immunology, University of Melbourne, Peter Doherty Institute for Infection and Immunity, Melbourne, VIC 3000, Australia
| | - Jeffrey Y W Mak
- Division of Chemistry and Structural Biology, Institute for Molecular Bioscience, University of Queensland, Saint Lucia, QLD 4072, Australia.,Australian Research Council Centre of Excellence in Advanced Molecular Imaging, University of Queensland, Saint Lucia, QLD 4072, Australia
| | - David P Fairlie
- Division of Chemistry and Structural Biology, Institute for Molecular Bioscience, University of Queensland, Saint Lucia, QLD 4072, Australia.,Australian Research Council Centre of Excellence in Advanced Molecular Imaging, University of Queensland, Saint Lucia, QLD 4072, Australia
| | - Michele W L Teng
- QIMR Berghofer Medical Research Institute, Herston, QLD 4006, Australia
| | - Jamie Rossjohn
- Infection and Immunity Program and the Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Clayton, VIC 3800, Australia.,Australian Research Council Centre of Excellence in Advanced Molecular Imaging, Monash University, Clayton, VIC 3800, Australia.,Institute of Infection and Immunity, Cardiff University, School of Medicine, Heath Park, CF14 4XN Wales, UK
| | - Di Yu
- John Curtin School of Medical Research, The Australian National University, Acton, ACT 2601 Australia
| | - Barbara Fazekas de St Groth
- Discipline of Pathology, Charles Perkins Centre, Faculty of Medicine and Health, University of Sydney, Sydney, NSW 2006, Australia
| | - George Lovrecz
- Biomedical Manufacturing, CSIRO, Parkville, VIC, 3052, Australia
| | - Louis Lu
- Biomedical Manufacturing, CSIRO, Parkville, VIC, 3052, Australia
| | - James McCluskey
- Department of Microbiology and Immunology, University of Melbourne, Peter Doherty Institute for Infection and Immunity, Melbourne, VIC 3000, Australia
| | - Richard A Strugnell
- Department of Microbiology and Immunology, University of Melbourne, Peter Doherty Institute for Infection and Immunity, Melbourne, VIC 3000, Australia.
| | - Alexandra J Corbett
- Department of Microbiology and Immunology, University of Melbourne, Peter Doherty Institute for Infection and Immunity, Melbourne, VIC 3000, Australia.
| | - Zhenjun Chen
- Department of Microbiology and Immunology, University of Melbourne, Peter Doherty Institute for Infection and Immunity, Melbourne, VIC 3000, Australia.
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28
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Sproat T, Payne RP, Embleton ND, Berrington J, Hambleton S. T Cells in Preterm Infants and the Influence of Milk Diet. Front Immunol 2020; 11:1035. [PMID: 32582165 PMCID: PMC7280433 DOI: 10.3389/fimmu.2020.01035] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2019] [Accepted: 04/29/2020] [Indexed: 12/22/2022] Open
Abstract
Preterm infants born before 32 weeks gestational age (GA) have high rates of late onset sepsis (LOS) and necrotizing enterocolitis (NEC) despite recent improvements in infection control and nutrition. Breast milk has a clear protective effect against both these outcomes likely due to multiple mechanisms which are not fully understood but may involve effects on both the infant's immune system and the developing gut microbiota. Congregating at the interface between the mucosal barrier and the microbiota, innate and adaptive T lymphocytes (T cells) participate in this interaction but few studies have explored their development after preterm delivery. We conducted a literature review of T cell development that focuses on fetal development, postnatal maturation and the influence of milk diet. The majority of circulating T cells in the preterm infant display a naïve phenotype but are still able to initiate functional responses similar to those seen in term infants. T cells from preterm infants display a skew toward a T-helper 2(Th2) phenotype and have an increased population of regulatory cells (Tregs). There are significant gaps in knowledge in this area, particularly in regards to innate-like T cells, but work is emerging: transcriptomics and mass cytometry are currently being used to map out T cell development, whilst microbiomic approaches may help improve understanding of events at mucosal surfaces. A rapid rise in organoid models will allow robust exploration of host-microbe interactions and may support the development of interventions that modulate T-cell responses for improved infant health.
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Affiliation(s)
- Thomas Sproat
- Neonatal Intensive Care Unit, Royal Victoria Infirmary, Newcastle upon Tyne, United Kingdom
- Immunity and Inflammation Theme, Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, United Kingdom
| | - Rebecca Pamela Payne
- Immunity and Inflammation Theme, Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, United Kingdom
| | - Nicholas D. Embleton
- Neonatal Intensive Care Unit, Royal Victoria Infirmary, Newcastle upon Tyne, United Kingdom
- Population Health Science Institute, Newcastle University, Newcastle upon Tyne, United Kingdom
| | - Janet Berrington
- Neonatal Intensive Care Unit, Royal Victoria Infirmary, Newcastle upon Tyne, United Kingdom
- Immunity and Inflammation Theme, Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, United Kingdom
| | - Sophie Hambleton
- Immunity and Inflammation Theme, Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, United Kingdom
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29
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Collin R, Lombard-Vadnais F, Hillhouse EE, Lebel MÈ, Chabot-Roy G, Melichar HJ, Lesage S. MHC-Independent Thymic Selection of CD4 and CD8 Coreceptor Negative αβ T Cells. THE JOURNAL OF IMMUNOLOGY 2020; 205:133-142. [PMID: 32434937 DOI: 10.4049/jimmunol.2000156] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/10/2020] [Accepted: 04/23/2020] [Indexed: 12/12/2022]
Abstract
It is becoming increasingly clear that unconventional T cell subsets, such as NKT, γδ T, mucosal-associated invariant T, and CD8αα T cells, each play distinct roles in the immune response. Subsets of these cell types can lack both CD4 and CD8 coreceptor expression. Beyond these known subsets, we identify CD4-CD8-TCRαβ+, double-negative (DN) T cells, in mouse secondary lymphoid organs. DN T cells are a unique unconventional thymic-derived T cell subset. In contrast to CD5high DN thymocytes that preferentially yield TCRαβ+ CD8αα intestinal lymphocytes, we find that mature CD5low DN thymocytes are precursors to peripheral DN T cells. Using reporter mouse strains, we show that DN T cells transit through the immature CD4+CD8+ (double-positive) thymocyte stage. Moreover, we provide evidence that DN T cells can differentiate in MHC-deficient mice. Our study demonstrates that MHC-independent thymic selection can yield DN T cells that are distinct from NKT, γδ T, mucosal-associated invariant T, and CD8αα T cells.
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Affiliation(s)
- Roxanne Collin
- Immunology-Oncology Section, Maisonneuve-Rosemont Hospital Research Center, Montreal, Quebec H1T 2M4, Canada.,Département de Microbiologie, Infectiologie et Immunologie, Université de Montréal, Montreal, Quebec H3C 3J7, Canada
| | - Félix Lombard-Vadnais
- Immunology-Oncology Section, Maisonneuve-Rosemont Hospital Research Center, Montreal, Quebec H1T 2M4, Canada.,Department of Microbiology and Immunology, McGill University, Montreal, Quebec H3A 0G4, Canada; and
| | - Erin E Hillhouse
- Immunology-Oncology Section, Maisonneuve-Rosemont Hospital Research Center, Montreal, Quebec H1T 2M4, Canada
| | - Marie-Ève Lebel
- Immunology-Oncology Section, Maisonneuve-Rosemont Hospital Research Center, Montreal, Quebec H1T 2M4, Canada
| | - Geneviève Chabot-Roy
- Immunology-Oncology Section, Maisonneuve-Rosemont Hospital Research Center, Montreal, Quebec H1T 2M4, Canada
| | - Heather J Melichar
- Immunology-Oncology Section, Maisonneuve-Rosemont Hospital Research Center, Montreal, Quebec H1T 2M4, Canada.,Département de Médecine, Université de Montréal, Montreal, Quebec H3T 1J4, Canada
| | - Sylvie Lesage
- Immunology-Oncology Section, Maisonneuve-Rosemont Hospital Research Center, Montreal, Quebec H1T 2M4, Canada; .,Département de Microbiologie, Infectiologie et Immunologie, Université de Montréal, Montreal, Quebec H3C 3J7, Canada
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30
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Awad W, Ler GJM, Xu W, Keller AN, Mak JYW, Lim XY, Liu L, Eckle SBG, Le Nours J, McCluskey J, Corbett AJ, Fairlie DP, Rossjohn J. The molecular basis underpinning the potency and specificity of MAIT cell antigens. Nat Immunol 2020; 21:400-411. [PMID: 32123373 DOI: 10.1038/s41590-020-0616-6] [Citation(s) in RCA: 50] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2019] [Accepted: 01/23/2020] [Indexed: 01/24/2023]
Abstract
Mucosal-associated invariant T (MAIT) cells are activated by microbial riboflavin-based metabolite antigens when presented by MR1. How modifications to the potent antigen 5-OP-RU affect presentation by MR1 and MAIT cell activation remains unclear. Here we design 20 derivatives, termed altered metabolite ligands (AMLs), to dissect the impact of different antigen components on the human MAIT-MR1 axis. Analysis of 11 crystal structures of MAIT T cell antigen receptor (TCR)-MR1-AML ternary complexes, along with biochemical and functional assays, shows that MR1 cell-surface upregulation is influenced by ribityl and non-ribityl components of the ligand and the hydrophobicity of the MR1-AML interface. The polar ribityl chain of the AML strongly influences MAIT cell activation potency through dynamic compensatory interactions within a MAIT TCR-MR1-AML interaction triad. We define the basis by which the MAIT TCR can differentially recognize AMLs, thereby providing insight into MAIT cell antigen specificity and potency.
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Affiliation(s)
- Wael Awad
- Infection and Immunity Program and Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Clayton, Victoria, Australia.,ARC Centre of Excellence in Advanced Molecular Imaging, Monash University, Clayton, Victoria, Australia
| | - Geraldine J M Ler
- Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland, Australia.,ARC Centre of Excellence in Advanced Molecular Imaging, University of Queensland, Brisbane, Queensland, Australia
| | - Weijun Xu
- Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland, Australia.,ARC Centre of Excellence in Advanced Molecular Imaging, University of Queensland, Brisbane, Queensland, Australia
| | - Andrew N Keller
- Infection and Immunity Program and Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Clayton, Victoria, Australia.,ARC Centre of Excellence in Advanced Molecular Imaging, Monash University, Clayton, Victoria, Australia
| | - Jeffrey Y W Mak
- Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland, Australia.,ARC Centre of Excellence in Advanced Molecular Imaging, University of Queensland, Brisbane, Queensland, Australia
| | - Xin Yi Lim
- Department of Microbiology and Immunology, Peter Doherty Institute for Infection and Immunity, University of Melbourne, Melbourne, Victoria, Australia
| | - Ligong Liu
- Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland, Australia.,ARC Centre of Excellence in Advanced Molecular Imaging, University of Queensland, Brisbane, Queensland, Australia
| | - Sidonia B G Eckle
- Department of Microbiology and Immunology, Peter Doherty Institute for Infection and Immunity, University of Melbourne, Melbourne, Victoria, Australia
| | - Jérôme Le Nours
- Infection and Immunity Program and Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Clayton, Victoria, Australia.,ARC Centre of Excellence in Advanced Molecular Imaging, Monash University, Clayton, Victoria, Australia
| | - James McCluskey
- Department of Microbiology and Immunology, Peter Doherty Institute for Infection and Immunity, University of Melbourne, Melbourne, Victoria, Australia
| | - Alexandra J Corbett
- Department of Microbiology and Immunology, Peter Doherty Institute for Infection and Immunity, University of Melbourne, Melbourne, Victoria, Australia.
| | - David P Fairlie
- Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland, Australia. .,ARC Centre of Excellence in Advanced Molecular Imaging, University of Queensland, Brisbane, Queensland, Australia.
| | - Jamie Rossjohn
- Infection and Immunity Program and Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Clayton, Victoria, Australia. .,ARC Centre of Excellence in Advanced Molecular Imaging, Monash University, Clayton, Victoria, Australia. .,Institute of Infection and Immunity, Cardiff University School of Medicine, Cardiff, UK.
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31
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Khan S, Chan YT, Revelo XS, Winer DA. The Immune Landscape of Visceral Adipose Tissue During Obesity and Aging. Front Endocrinol (Lausanne) 2020; 11:267. [PMID: 32499756 PMCID: PMC7243349 DOI: 10.3389/fendo.2020.00267] [Citation(s) in RCA: 58] [Impact Index Per Article: 11.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/16/2020] [Accepted: 04/14/2020] [Indexed: 12/16/2022] Open
Abstract
Obesity and aging represent major health burdens to the global adult population. Both conditions promote the development of associated metabolic diseases such as insulin resistance. The visceral adipose tissue (VAT) is a site that becomes dysfunctional during obesity and aging, and plays a significant role during their pathophysiology. The changes in obese and aging VAT are now recognized to be partly driven by a chronic local inflammatory state, characterized by immune cells that typically adopt an inflammatory phenotype during metabolic disease. Here, we summarize the current knowledge on the immune cell landscape of the VAT during lean, obese, and aged conditions, highlighting their similarities and differences. We also briefly discuss possible linked mechanisms that fuel obesity- and age-associated VAT dysfunction.
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Affiliation(s)
- Saad Khan
- Department of Immunology, University of Toronto, Toronto, ON, Canada
- Division of Cellular & Molecular Biology, Diabetes Research Group, Toronto General Hospital Research Institute (TGHRI), University Health Network, Toronto, ON, Canada
| | - Yi Tao Chan
- Department of Immunology, University of Toronto, Toronto, ON, Canada
- Division of Cellular & Molecular Biology, Diabetes Research Group, Toronto General Hospital Research Institute (TGHRI), University Health Network, Toronto, ON, Canada
| | - Xavier S. Revelo
- Center for Immunology, University of Minnesota, Minneapolis, MN, United States
- Department of Integrative Biology and Physiology, University of Minnesota, Minneapolis, MN, United States
- *Correspondence: Xavier S. Revelo
| | - Daniel A. Winer
- Department of Immunology, University of Toronto, Toronto, ON, Canada
- Division of Cellular & Molecular Biology, Diabetes Research Group, Toronto General Hospital Research Institute (TGHRI), University Health Network, Toronto, ON, Canada
- Department of Pathology, University Health Network, Toronto, ON, Canada
- Buck Institute for Research on Aging, Novato, CA, United States
- Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada
- Daniel A. Winer
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Kwak HD, Ju JK. Immunological Differences Between Right-Sided and Left-Sided Colorectal Cancers: A Comparison of Embryologic Midgut and Hindgut. Ann Coloproctol 2019; 35:342-346. [PMID: 31937074 PMCID: PMC6968724 DOI: 10.3393/ac.2019.03.17.1] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/10/2019] [Accepted: 03/17/2019] [Indexed: 02/06/2023] Open
Abstract
Purpose There are known differences in embryology, clinical symptoms, incidences, molecular pathways involved, and oncologic outcomes of right-sided and left-sided colorectal cancers. However, immunologic study has only been characterized for healthy adults. The present study was designed to identify differences in immune cell populations in patients with right-sided and left-sided colorectal cancers. Methods A total of 35 patients who underwent colorectal resection for cancer between November 2016 and August 2017 at a tertiary teaching hospital were enrolled in this study. Patients were excluded if they had a disease affecting their immune system. Populations of immune cells, including mucosal-associated invariant T (MAIT), gamma delta T, invariant natural killer T, T, natural killer, and B cells, were measured in the peripheral blood and cancer tissues using flow cytometry, and then assessed based on the origin of the colorectal cancer. Results Fifteen had right-side and 20 had left-side colorectal cancer. There were no significant differences between the 2 cohorts for patient characteristics including pathologic stage. Peripheral blood from patients with right-side colon cancers contained fewer MAIT (0.87% right-side vs. 1.74% left-side, P = 0.028) and gamma delta T cells (1.10% right-side vs. 3.05% left-side, P = 0.002). Although the group with right-side colorectal cancer had more MAIT cells in cancer tissues (1.71% vs. 1.00%), this difference was not statistically significant. Conclusion There is a difference in population sizes of immune cells in blood between patients with right-sided and leftsided colon cancers. The immune cell composition was determined to be distinct based on embryologic origin.
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Affiliation(s)
- Han Deok Kwak
- Department of Surgery, Chonnam National University Hospital, Gwangju, Korea
| | - Jae Kyun Ju
- Department of Surgery, Chonnam National University Hospital, Gwangju, Korea
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Yan J, Allen S, McDonald E, Das I, Mak JYW, Liu L, Fairlie DP, Meehan BS, Chen Z, Corbett AJ, Varelias A, Smyth MJ, Teng MWL. MAIT Cells Promote Tumor Initiation, Growth, and Metastases via Tumor MR1. Cancer Discov 2019; 10:124-141. [PMID: 31826876 DOI: 10.1158/2159-8290.cd-19-0569] [Citation(s) in RCA: 100] [Impact Index Per Article: 16.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2019] [Revised: 09/09/2019] [Accepted: 10/18/2019] [Indexed: 11/16/2022]
Abstract
Mucosal-associated invariant T (MAIT) cells are innate-like T cells that require MHC class I-related protein 1 (MR1) for their development. The role of MAIT cells in cancer is unclear, and to date no study has evaluated these cells in vivo in this context. Here, we demonstrated that tumor initiation, growth, and experimental lung metastasis were significantly reduced in Mr1 -/- mice, compared with wild-type mice. The antitumor activity observed in Mr1 -/- mice required natural killer (NK) and/or CD8+ T cells and IFNγ. Adoptive transfer of MAIT cells into Mr1 -/- mice reversed metastasis reduction. Similarly, MR1-blocking antibodies decreased lung metastases and suppressed tumor growth. Following MR1 ligand exposure, some, but not all, mouse and human tumor cell lines upregulated MR1. Pretreatment of tumor cells with the stimulatory ligand 5-OP-RU or inhibitory ligand Ac-6-FP increased or decreased lung metastases, respectively. MR1-deleted tumors resulted in fewer metastases compared with parental tumor cells. MAIT cell suppression of NK-cell effector function was tumor-MR1-dependent and partially required IL17A. Our studies indicate that MAIT cells display tumor-promoting function by suppressing T and/or NK cells and that blocking MR1 may represent a new therapeutic strategy for cancer immunotherapy. SIGNIFICANCE: Contradicting the perception that MAIT cells kill tumor cells, here MAIT cells promoted tumor initiation, growth, and metastasis. MR1-expressing tumor cells activated MAIT cells to reduce NK-cell effector function, partly in a host IL17A-dependent manner. MR1-blocking antibodies reduced tumor metastases and growth, and may represent a new class of cancer therapeutics.This article is highlighted in the In This Issue feature, p. 1.
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Affiliation(s)
- Juming Yan
- Cancer Immunoregulation and Immunotherapy Laboratory, QIMR Berghofer Medical Research Institute, Herston, Australia
- School of Medicine, University of Queensland, Herston, Australia
| | - Stacey Allen
- Cancer Immunoregulation and Immunotherapy Laboratory, QIMR Berghofer Medical Research Institute, Herston, Australia
| | - Elizabeth McDonald
- Cancer Immunoregulation and Immunotherapy Laboratory, QIMR Berghofer Medical Research Institute, Herston, Australia
| | - Indrajit Das
- Immunology in Cancer and Infection Laboratory, QIMR Berghofer Medical Research Institute, Herston, Australia
| | - Jeffrey Y W Mak
- Division of Chemistry and Structural Biology, Institute for Molecular Bioscience, The University of Queensland, Brisbane, Australia
- ARC Centre of Excellence in Advanced Molecular Imaging, University of Queensland, Brisbane, Australia
| | - Ligong Liu
- Division of Chemistry and Structural Biology, Institute for Molecular Bioscience, The University of Queensland, Brisbane, Australia
- ARC Centre of Excellence in Advanced Molecular Imaging, University of Queensland, Brisbane, Australia
| | - David P Fairlie
- Division of Chemistry and Structural Biology, Institute for Molecular Bioscience, The University of Queensland, Brisbane, Australia
- ARC Centre of Excellence in Advanced Molecular Imaging, University of Queensland, Brisbane, Australia
| | - Bronwyn S Meehan
- Department of Microbiology and Immunology, The University of Melbourne, The Peter Doherty Institute for Infection and Immunity, Victoria, Australia
| | - Zhenjun Chen
- Department of Microbiology and Immunology, The University of Melbourne, The Peter Doherty Institute for Infection and Immunity, Victoria, Australia
| | - Alexandra J Corbett
- Department of Microbiology and Immunology, The University of Melbourne, The Peter Doherty Institute for Infection and Immunity, Victoria, Australia
| | - Antiopi Varelias
- School of Medicine, University of Queensland, Herston, Australia
- Transplantation Immunology Laboratory, QIMR Berghofer Medical Research Institute, Brisbane, Australia
| | - Mark J Smyth
- School of Medicine, University of Queensland, Herston, Australia
- Immunology in Cancer and Infection Laboratory, QIMR Berghofer Medical Research Institute, Herston, Australia
| | - Michele W L Teng
- Cancer Immunoregulation and Immunotherapy Laboratory, QIMR Berghofer Medical Research Institute, Herston, Australia.
- School of Medicine, University of Queensland, Herston, Australia
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Pan Y, Deng W, Xie J, Zhang S, Wan ECK, Li L, Tao H, Hu Z, Chen Y, Ma L, Gao J, Zhong XP. Graded diacylglycerol kinases α and ζ activities ensure mucosal-associated invariant T-cell development in mice. Eur J Immunol 2019; 50:192-204. [PMID: 31710099 DOI: 10.1002/eji.201948289] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2019] [Revised: 08/27/2019] [Accepted: 11/07/2019] [Indexed: 01/22/2023]
Abstract
Mucosal-associated invariant T (MAIT) cells participate in both protective immunity and pathogenesis of diseases. Most murine MAIT cells express an invariant TCRVα19-Jα33 (iVα19) TCR, which triggers signals crucial for their development. However, signal pathways downstream of the iVα19TCR and their regulation in MAIT cells are unknown. Diacylglycerol (DAG) is a critical second messenger that relays the TCR signal to multiple downstream signaling cascades. DAG is terminated by DAG kinase (DGK)-mediated phosphorylation and conversion to phosphatidic acid. We have demonstrated here that downregulation of DAG caused by enhanced DGK activity impairs late-stage MAIT cell maturation in both thymus and spleen. Moreover, deficiency of DGKζ but not DGKα by itself causes modest decreases in MAIT cells, and deficiency of both DGKα and ζ results in severe reductions of MAIT cells in an autonomous manner. Our studies have revealed that DAG signaling is not only critical but also must be tightly regulated by DGKs for MAIT cell development and that both DGKα and, more prominently, DGKζ contribute to the overall DGK activity for MAIT cell development.
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Affiliation(s)
- Yun Pan
- Department of Pediatrics-Allergy and Immunology, Duke University Medical Center, Durham, NC.,School of Laboratory Medicine, Wenzhou Medical University, Wenzhou, Zhejiang Province, China
| | - Wenhai Deng
- Department of Pediatrics-Allergy and Immunology, Duke University Medical Center, Durham, NC.,School of Laboratory Medicine, Wenzhou Medical University, Wenzhou, Zhejiang Province, China
| | - Jinhai Xie
- School of Laboratory Medicine, Wenzhou Medical University, Wenzhou, Zhejiang Province, China
| | - Shimeng Zhang
- Department of Pediatrics-Allergy and Immunology, Duke University Medical Center, Durham, NC.,Institute of Molecular Immunology, School of Laboratory Medicine and Biotechnology, Southern Medical University, Guangzhou, China
| | - Edwin C K Wan
- Department of Pediatrics-Allergy and Immunology, Duke University Medical Center, Durham, NC.,Department of Microbiology, Immunology, & Cell Biology and Department of Neuroscience, West Virginia University, Morgantown, WV
| | - Lei Li
- Department of Pediatrics-Allergy and Immunology, Duke University Medical Center, Durham, NC.,Department of Breast and Thyroid Surgery and Department of Gynecology and Obstetrics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Huishan Tao
- Department of Pediatrics-Allergy and Immunology, Duke University Medical Center, Durham, NC.,Department of Gynecology and Obstetrics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Zhiming Hu
- Department of Pediatrics-Allergy and Immunology, Duke University Medical Center, Durham, NC.,Institute of Molecular Immunology, School of Laboratory Medicine and Biotechnology, Southern Medical University, Guangzhou, China
| | - Yongping Chen
- Department of Infectious Diseases, the First Affiliated Hospital of Wenzhou Medical University and Wenzhou Key Laboratory of Hepatology, Hepatology Institute of Wenzhou Medical University, Wenzhou, China
| | - Li Ma
- Institute of Molecular Immunology, School of Laboratory Medicine and Biotechnology, Southern Medical University, Guangzhou, China
| | - Jimin Gao
- School of Laboratory Medicine, Wenzhou Medical University, Wenzhou, Zhejiang Province, China
| | - Xiao-Ping Zhong
- Department of Pediatrics-Allergy and Immunology, Duke University Medical Center, Durham, NC.,Department of Immunology and Duke Cancer Institute, Duke University Medical Center, Durham, NC.,Duke Cancer Institute, Duke University Medical Center, Durham, NC
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Zhang CX, Wang HY, Chen TX. Interactions between Intestinal Microflora/Probiotics and the Immune System. BIOMED RESEARCH INTERNATIONAL 2019; 2019:6764919. [PMID: 31828119 PMCID: PMC6886316 DOI: 10.1155/2019/6764919] [Citation(s) in RCA: 54] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 06/28/2019] [Revised: 10/24/2019] [Accepted: 11/04/2019] [Indexed: 12/13/2022]
Abstract
The digestive tract is home to millions of microorganisms and is the main and most important part of bacterial colonization. On one hand, the abundant bacterial community in intestinal tissues may pose potential health challenges such as inflammation and sepsis in cases of opportunistic invasion. Thus, the immune system has evolved and adapted to maintain the symbiotic relationship between host and microbiota. On the other hand, the intestinal microflora also exerts an immunoregulatory function to maintain host immune homeostasis, which cannot be neglected. In addition, the interaction of either microbiota or probiotics with immune system in regard to therapeutic applications is an area of great interest, and novel therapeutic strategies remain to be investigated. The review will elucidate interactions between intestinal microflora/probiotics and the immune system as well as novel therapeutic strategies.
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Affiliation(s)
- Chen-xing Zhang
- Department of Rheumatology and Immunology, Shanghai Children's Medical Center Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Department of Nephrology, Shanghai Children's Medical Center Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Division of Immunology, Institute of Pediatric Translational Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Hui-yu Wang
- Institute of Physiological Chemistry and Pathobiochemistry, University of Muenster, Muenster, Germany
| | - Tong-xin Chen
- Department of Rheumatology and Immunology, Shanghai Children's Medical Center Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Division of Immunology, Institute of Pediatric Translational Medicine, Shanghai Jiao Tong University, Shanghai, China
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Raychaudhuri SK, Abria C, Mitra A, Raychaudhuri SP. Functional significance of MAIT cells in psoriatic arthritis. Cytokine 2019; 125:154855. [PMID: 31541902 DOI: 10.1016/j.cyto.2019.154855] [Citation(s) in RCA: 33] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2019] [Revised: 09/08/2019] [Accepted: 09/09/2019] [Indexed: 02/06/2023]
Abstract
BACKGROUND Mucosal-associated invariant T (MAIT) cells are gaining more relevance for autoimmune diseases because of its (i) innate and adaptive immune response (ii) tissue homing properties (iii) production of IL-17A. These cells are predominantly CD8+ cells, because of its strong association with MHC-I. Tc17 CD8+/MAIT cells likely to have a critical role in psoriatic arthritis (PsA). Herein, we have explored pathological significance of MAIT cell in PsA. METHODS Peripheral blood mononuclear cells (PBMC) and synovial fluid mononuclear cells (SFMC) were collected from age/sex matched (n = 10 for each) PsA, rheumatoid arthritis (RA) and osteoarthritis patients (OA). Hi-D FACS studies were performed: (i) activated memory cells (CD3+CD45RO+) T cells were identified (ii) gating strategies were made to identity the MAIT (CD3+Vα7.2TCR+CD161hi) cells, its phenotype pattern; and functional significance in respect to IL-17A production and responsiveness to human rIL-23. Anti CD3/CD28 ab cocktail was used to activate cells along with rIL-23 to culture and enrich the MAIT cells. The percentages of each cell population and the mean fluorescence intensity (MFI) were analyzed using Flow Jo software. RESULTS MAIT cells were enriched in synovial fluid of PsA (4.29 ± 0.82%) compared to PBMC (1.04 ± 0.71). With stimulation, SFMC MAIT cells produced significantly more IL-17A (32.66 ± 4.01%) compared to that of RA (23.93 ± 2.81%, p < 0.05) and OA (5.02 ± 0.16%, p < 0.05). MAIT cells were predominantly CD8+ (>80%). Significant upregulation of IL-23R was noted in synovial fluid MAIT cells of PsA (24.97 ± 2.33%, p < 0.001) and RA (21.93 ± 2.29%, p < 0.001) compared to that of OA (2.13 ± 2.29). This IL-23R was functionally active as evidenced by profound mitotic effect in presence of rIL-23. CONCLUSION MAIT cells are poly functional; produce multiple cytokines (IL-17A, IFN-γ, TNF-α). Here, we demonstrated synovial fluid MAIT cells as a major source of IL-17A and majority of MAIT cells were CD8+. Functionally active IL-23R on these migrated MAIT cells brings a new dimension. They may not need MR1 associated activation rather lesional IL-23 in the synovium can independently regulate these critical Tc17 CD8+ MAIT cells. Thus, these cells likely to be a part of the IL-23/IL-17A cytokine network and play a critical role in the pathogenesis of PsA.
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Affiliation(s)
| | | | | | - Siba P Raychaudhuri
- VA Medical Center Sacramento, CA, USA; Division of Rheumatology, Allergy & Clinical Immunology, University of California Davis, School of Medicine Sacramento, CA, USA.
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Merlini E, Cerrone M, van Wilgenburg B, Swadling L, Cannizzo ES, d'Arminio Monforte A, Klenerman P, Marchetti G. Association Between Impaired Vα7.2+CD161++CD8+ (MAIT) and Vα7.2+CD161-CD8+ T-Cell Populations and Gut Dysbiosis in Chronically HIV- and/or HCV-Infected Patients. Front Microbiol 2019; 10:1972. [PMID: 31555223 PMCID: PMC6722213 DOI: 10.3389/fmicb.2019.01972] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2019] [Accepted: 08/12/2019] [Indexed: 01/06/2023] Open
Abstract
Both HIV and HCV infections feature increased microbial translocation (MT) and gut dysbiosis that affect immune homeostasis and disease outcome. Given their commitment to antimicrobial mucosal immunity, we investigated mucosal-associated invariant T (MAIT) cells and Vα7.2+CD161- T-cell frequency/function and their possible associations with MT and gut dysbiosis, in chronic HIV and/or HCV infections. We enrolled 56 virally infected (VI) patients (pts): 13 HIV+ on suppressive cART (HIV-RNA < 40cp/ml), 13 HCV+ naive to DAA (direct-acting antiviral) anti-HCV agents; 30 HCV+/HIV+ on suppressive cART and naive to anti-HCV. 13 age-matched healthy controls (HC) were enrolled. For Vα7.2+CD161++ and Vα7.2+CD161-CD8+ T cells we assessed: activation (CD69), exhaustion (PD1/CD39), and cytolytic activity (granzymeB/perforin). Following PMA/ionomycin and Escherichia coli stimulation we measured intracellular IL17/TNFα/IFNγ. Markers of microbial translocation (Plasma LPS, 16S rDNA, EndoCAb and I-FABP) were quantified. In 5 patients per group we assessed stool microbiota composition by 16S targeted metagenomics sequencing (alpha/beta diversity, relative abundance). Compared to controls, virally infected pts displayed significantly lower circulating Vα7.2+CD161++CD8+ MAIT cells (p = 0.001), yet expressed higher perforin (p = 0.004) and granzyme B (p = 0.002) on CD8+ MAIT cells. Upon E. coli stimulation, the residual MAIT cells are less functional particularly those from HIV+/HCV+ patients. Conversely, in virally infected pts, Vα7.2+CD161-CD8+ cells were comparable in frequency, highly activated/exhausted (CD69+: p = 0.002; PD-1+: p = 0.030) and with cytolytic potential (perforin+: p < 0.0001), yet were poorly responsive to ex vivo stimulation. A profound gut dysbiosis characterized virally infected pts, especially HCV+/HIV+ co-infected patients, delineating a Firmicutes-poor/Bacteroidetes-rich microbiota, with significant associations with MAIT cell frequency/function. Irrespective of mono/dual infection, HIV+ and HCV+ patients display depleted, yet activated/cytolytic MAIT cells with reduced ex vivo function, suggesting an impoverished pool, possibly due to continuous bacterial challenge. The MAIT cell ability to respond to bacterial stimulation correlates with the presence of Firmicutes and Bacteroidetes, possibly suggesting an association between gut dysbiosis and MAIT cell function and posing viral-mediated dysbiosis as a potential key player in the hampered anti-bacterial MAIT ability.
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Affiliation(s)
- Esther Merlini
- Department of Health Sciences, Clinic of Infectious Diseases, ASST Santi Paolo e Carlo, University of Milan, Milan, Italy
| | - Maddalena Cerrone
- Department of Health Sciences, Clinic of Infectious Diseases, ASST Santi Paolo e Carlo, University of Milan, Milan, Italy.,Chelsea and Westminster Hospital NHS Foundation Trust, London, United Kingdom
| | - Bonnie van Wilgenburg
- Peter Medawar Building for Pathogen Research, University of Oxford, Oxford, United Kingdom
| | - Leo Swadling
- Peter Medawar Building for Pathogen Research, University of Oxford, Oxford, United Kingdom
| | - E Stefania Cannizzo
- Department of Health Sciences, Clinic of Infectious Diseases, ASST Santi Paolo e Carlo, University of Milan, Milan, Italy
| | - Antonella d'Arminio Monforte
- Department of Health Sciences, Clinic of Infectious Diseases, ASST Santi Paolo e Carlo, University of Milan, Milan, Italy
| | - Paul Klenerman
- Peter Medawar Building for Pathogen Research, University of Oxford, Oxford, United Kingdom
| | - Giulia Marchetti
- Department of Health Sciences, Clinic of Infectious Diseases, ASST Santi Paolo e Carlo, University of Milan, Milan, Italy
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Lezmi G, Abou-Taam R, Garcelon N, Dietrich C, Machavoine F, Delacourt C, Adel-Patient K, Leite-de-Moraes M. Evidence for a MAIT-17-high phenotype in children with severe asthma. J Allergy Clin Immunol 2019; 144:1714-1716.e6. [PMID: 31425779 DOI: 10.1016/j.jaci.2019.08.003] [Citation(s) in RCA: 27] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2019] [Revised: 07/19/2019] [Accepted: 08/02/2019] [Indexed: 11/28/2022]
Affiliation(s)
- Guillaume Lezmi
- AP-HP, Hôpital Necker-Enfants Malades, Service de Pneumologie et Allergologie Pédiatriques, Paris, France; Université Paris Descartes, Paris, France; Laboratory of Immunoregulation and Immunopathology, INEM (Institut Necker-Enfants Malades), CNRS UMR8253 and INSERM UMR1151, Paris, France.
| | - Rola Abou-Taam
- AP-HP, Hôpital Necker-Enfants Malades, Service de Pneumologie et Allergologie Pédiatriques, Paris, France; Université Paris Descartes, Paris, France
| | - Nicolas Garcelon
- Institut Imagine, Université Paris Descartes-Sorbonne Paris Cité, Paris, France
| | - Céline Dietrich
- Université Paris Descartes, Paris, France; Laboratory of Immunoregulation and Immunopathology, INEM (Institut Necker-Enfants Malades), CNRS UMR8253 and INSERM UMR1151, Paris, France
| | - François Machavoine
- Université Paris Descartes, Paris, France; Laboratory of Immunoregulation and Immunopathology, INEM (Institut Necker-Enfants Malades), CNRS UMR8253 and INSERM UMR1151, Paris, France
| | - Christophe Delacourt
- AP-HP, Hôpital Necker-Enfants Malades, Service de Pneumologie et Allergologie Pédiatriques, Paris, France; Université Paris Descartes, Paris, France
| | - Karine Adel-Patient
- UMR Service de Pharmacologie et d'Immunoanalyse, INRA, CEA, Université Paris-Saclay, Laboratoire d'Immuno-Allergie Alimentaire, Gif-sur-Yvette, France
| | - Maria Leite-de-Moraes
- Université Paris Descartes, Paris, France; Laboratory of Immunoregulation and Immunopathology, INEM (Institut Necker-Enfants Malades), CNRS UMR8253 and INSERM UMR1151, Paris, France.
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Huang Y, Mao K, Germain RN. Thinking differently about ILCs-Not just tissue resident and not just the same as CD4 + T-cell effectors. Immunol Rev 2019; 286:160-171. [PMID: 30294968 DOI: 10.1111/imr.12704] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2018] [Accepted: 08/10/2018] [Indexed: 12/16/2022]
Abstract
Innate lymphoid cells (ILCs) resemble adaptive T lymphocytes based on transcription factor expression, cytokine production, and their presumptive roles in immunity, but are activated for effector function through cytokine signaling and not antigen-specific receptors. The prevailing view is that ILCs adapt to specific microenvironments during development and operate as tissue-resident cells in co-operation with antigen-specific T cells to provide host protection and contribute to tissue maintenance. In particular, conventional models equate the activity of different ILC subsets with CD4+ effector T-cell types based on corresponding transcription factor expression and a potential for comparable cytokine production. Based on recent data from our laboratory, we suggest that these views on tissue residence and parallel functioning to CD4+ T cells are too restrictive. Our findings show that ILC2s can be mobilized from the gut under inflammatory conditions and contribute to distal immunity in the lungs during infection, whereas gut-resident ILC3s operate in a quite distinct manner from Th17 CD4+ effector cells in responding to commensal microbes, with important implications for control of metabolic homeostasis. In this review, we discuss the recent advances leading to these revised views of ILC inter-organ trafficking and the distinct and complementary function of ILCs with respect to adaptive T cells in establishing and maintaining a physiologic host environment.
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Affiliation(s)
- Yuefeng Huang
- Laboratory of Immune System Biology, National Institute of Allergy and Infectious Diseases, National institute of Health, Bethesda, Maryland.,Department of Microbiology & Immunology, College of Physicians & Surgeons, Columbia University, New York, New York
| | - Kairui Mao
- Laboratory of Immune System Biology, National Institute of Allergy and Infectious Diseases, National institute of Health, Bethesda, Maryland
| | - Ronald N Germain
- Laboratory of Immune System Biology, National Institute of Allergy and Infectious Diseases, National institute of Health, Bethesda, Maryland
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Xie J, Pan Y, Tao H, Wang P, Chen Y, Gao J, Zhong XP. Deficiency of Mucosal-Associated Invariant T Cells in TCRJα18 Germline Knockout Mice. Immunohorizons 2019; 3:203-207. [PMID: 31356166 DOI: 10.4049/immunohorizons.1900035] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2019] [Accepted: 05/31/2019] [Indexed: 11/19/2022] Open
Abstract
Mucosal-associated invariant T (MAIT) cells and invariant NK T (iNKT) cells account for the major lymphocyte populations that express invariant TCRα-chains. MAIT cells mostly express the TCRVα19-Jα33 TCR in mice and the TCRVα7.2-Jα33 TCR in humans, whereas iNKT cells express the TCRVα14-Jα18 TCR in mice and the TCRVα24-Jα18 TCR in humans. Both MAIT and iNKT cells have the capacity to quickly produce a variety of cytokines in response to agonist stimuli and to regulate both innate and adaptive immunity. The germline TCRJα18 knockout (Traj18-/- ) mice have been used extensively for studying iNKT cells. Although it has been reported that the TCRα repertoire was narrowed and the level of Trav19-ja33 transcript was decreased in this strain of mice, direct assessment of MAIT cells in these mice has not been reported. We demonstrate in this study that this strain of mice is also defective of MAIT T cells, cautioning data interpretation when using this strain of mice.
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Affiliation(s)
- Jinhai Xie
- Division of Allergy and Immunology, Department of Pediatrics, Duke University Medical Center, Durham, NC 27710.,School of Laboratory Medicine, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China
| | - Yun Pan
- School of Laboratory Medicine, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China
| | - Huishan Tao
- Division of Allergy and Immunology, Department of Pediatrics, Duke University Medical Center, Durham, NC 27710
| | - Peng Wang
- Division of Allergy and Immunology, Department of Pediatrics, Duke University Medical Center, Durham, NC 27710
| | - Yongping Chen
- Department of Infectious Diseases, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325035, China
| | - Jimin Gao
- School of Laboratory Medicine, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China;
| | - Xiao-Ping Zhong
- Division of Allergy and Immunology, Department of Pediatrics, Duke University Medical Center, Durham, NC 27710; .,Department of Immunology, Duke University Medical Center, Durham, NC 27710; and.,Hematologic Malignancies and Cellular Therapies Program, Duke Cancer Institute, Duke University Medical Center, Durham, NC 27710
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Jo YG, Jin HM, Cho YN, Kim JC, Kee SJ, Park YW. Activation and Impaired Tumor Necrosis Factor-α Production of Circulating Mucosal-Associated Invariant T Cells in Patients with Trauma. J Innate Immun 2019; 11:506-515. [PMID: 31085907 DOI: 10.1159/000499343] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2018] [Accepted: 02/28/2019] [Indexed: 01/20/2023] Open
Abstract
Mucosal-associated invariant T (MAIT) cells rapidly produce proinflammatory cytokines in an innate-like manner and play an important role in controlling the host immune response. This study examined the function of MAIT cells in trauma patients. The expression of cytokines in peripheral blood MAIT cells was measured by flow cytometry. MAIT cells in trauma patients displayed impaired tumor necrosis factor (TNF)-α production, together with elevated CD69 expression. The expression of CD69 was negatively correlated with MAIT cell frequency. These patients had higher plasma levels of interleukin (IL)-12 and IL-18. In particular, CD69 expression of MAIT cells was increased by stimulation with IL-18 in synergy with other proinflammatory cytokines or plasma of trauma patients. The production of TNF-α by MAIT cells was characterized by an initial burst and rapid decline, in contrast to delayed and sustained production of interferon (IFN)-γ. Activated MAIT cells showed a functional defect in the production of TNF-α upon restimulation. This study demonstrates that circulating MAIT cells are activated and functionally impaired in TNF-α production in patients with trauma. The activation and dysfunction of MAIT cells was mediated by proinflammatory cytokines. These findings provide important information underlying the innate immune response of patients with trauma.
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Affiliation(s)
- Young-Goun Jo
- Department of Surgery, Chonnam National University Medical School and Hospital, Gwangju, Republic of Korea
| | - Hye-Mi Jin
- Department of Rheumatology, Chonnam National University Medical School and Hospital, Gwangju, Republic of Korea
| | - Young-Nan Cho
- Department of Rheumatology, Chonnam National University Medical School and Hospital, Gwangju, Republic of Korea
| | - Jung-Chul Kim
- Department of Surgery, Chonnam National University Medical School and Hospital, Gwangju, Republic of Korea
| | - Seung-Jung Kee
- Department of Laboratory Medicine, Chonnam National University Medical School and Hospital, Gwangju, Republic of Korea
| | - Yong-Wook Park
- Department of Rheumatology, Chonnam National University Medical School and Hospital, Gwangju, Republic of Korea,
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Cannizzo ES, Cerrone M, Merlini E, van Wilgenburg B, Swadling L, Ancona G, De Bona A, d'Arminio Monforte A, Klenerman P, Marchetti G. Successful direct-acting antiviral therapy in HIV/HCV co-infected patients fails to restore circulating mucosal-associated invariant T cells. Eur J Immunol 2019; 49:1127-1129. [PMID: 30985000 DOI: 10.1002/eji.201948152] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2019] [Revised: 02/16/2019] [Accepted: 04/08/2019] [Indexed: 01/16/2023]
Affiliation(s)
- Elvira Stefania Cannizzo
- Department of Health Sciences, Clinic of Infectious Diseases, ASST Santi Paolo e Carlo, University of Milan, Milan, Italy
| | - Maddalena Cerrone
- Department of Health Sciences, Clinic of Infectious Diseases, ASST Santi Paolo e Carlo, University of Milan, Milan, Italy.,Imperial College London, London, UK
| | - Esther Merlini
- Department of Health Sciences, Clinic of Infectious Diseases, ASST Santi Paolo e Carlo, University of Milan, Milan, Italy
| | | | - Leo Swadling
- Peter Medawar Building for Pathogen Research, University of Oxford, Oxford, UK
| | - Giuseppe Ancona
- Department of Health Sciences, Clinic of Infectious Diseases, ASST Santi Paolo e Carlo, University of Milan, Milan, Italy
| | - Anna De Bona
- Department of Health Sciences, Clinic of Infectious Diseases, ASST Santi Paolo e Carlo, University of Milan, Milan, Italy
| | - Antonella d'Arminio Monforte
- Department of Health Sciences, Clinic of Infectious Diseases, ASST Santi Paolo e Carlo, University of Milan, Milan, Italy
| | - Paul Klenerman
- Peter Medawar Building for Pathogen Research, University of Oxford, Oxford, UK
| | - Giulia Marchetti
- Department of Health Sciences, Clinic of Infectious Diseases, ASST Santi Paolo e Carlo, University of Milan, Milan, Italy
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Kuo SH, Wu MS, Yeh KH, Lin CW, Hsu PN, Chen LT, Cheng AL. Novel Insights of Lymphomagenesis of Helicobacter pylori-Dependent Gastric Mucosa-Associated Lymphoid Tissue Lymphoma. Cancers (Basel) 2019; 11:547. [PMID: 30999581 PMCID: PMC6520890 DOI: 10.3390/cancers11040547] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2019] [Revised: 04/09/2019] [Accepted: 04/12/2019] [Indexed: 02/06/2023] Open
Abstract
Gastric mucosa-associated lymphoid tissue (MALT) lymphoma is the most common subtype of gastric lymphoma. Most gastric MALT lymphomas are characterized by their association with the Helicobacter pylori (HP) infection and are cured by first-line HP eradication therapy (HPE). Several studies have been conducted to investigate why most gastric MALT lymphomas remain localized, are dependent on HP infection, and show HP-specific intratumoral T-cells (e.g., CD40-mediated signaling, T-helper-2 (Th2)-type cytokines, chemokines, costimulatory molecules, and FOXP3+ regulatory T-cells) and their communication with B-cells. Furthermore, the reason why the antigen stimuli of these intratumoral T-cells with tonic B-cell receptor signaling promote lymphomagenesis of gastric MALT lymphoma has also been investigated. In addition to the aforementioned mechanisms, it has been demonstrated that the translocated HP cytotoxin-associated gene A (CagA) can promote B-cell proliferation through the activation of Src homology-2 domain-containing phosphatase (SHP-2) phosphorylation-dependent signaling, extracellular-signal-regulated kinase (ERK), p38 mitogen-activated protein kinase (MAPK), B-cell lymphoma (Bcl)-2, and Bcl-xL. Furthermore, the expression of CagA and these CagA-signaling molecules is closely associated with the HP-dependence of gastric MALT lymphomas (completely respond to first-line HPE). In this article, we summarize evidence of the classical theory of HP-reactive T-cells and the new paradigm of direct interaction between HP and B-cells that contributes to the HP-dependent lymphomagenesis of gastric MALT lymphomas. Although the role of first-line HPE in the treatment of HP-negative gastric MALT lymphoma remains uncertain, several case series suggest that a proportion of HP-negative gastric MALT lymphomas remains antibiotic-responsive and is cured by HPE. Considering the complicated interaction between microbiomes and the genome/epigenome, further studies on the precise mechanisms of HP- and other bacteria-directed lymphomagenesis in antibiotic-responsive gastric MALT lymphomas are warranted.
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Affiliation(s)
- Sung-Hsin Kuo
- Department of Oncology, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei 100, Taiwan.
- Cancer Research Center, National Taiwan University College of Medicine, Taipei 100, Taiwan.
- Graduate Institute of Oncology, National Taiwan University College of Medicine, Taipei 100, Taiwan.
- National Taiwan University Cancer Center, National Taiwan University College of Medicine, Taipei 106, Taiwan.
| | - Ming-Shiang Wu
- Department of Internal Medicine, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei 100, Taiwan.
| | - Kun-Huei Yeh
- Department of Oncology, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei 100, Taiwan.
- Cancer Research Center, National Taiwan University College of Medicine, Taipei 100, Taiwan.
- Graduate Institute of Oncology, National Taiwan University College of Medicine, Taipei 100, Taiwan.
- National Taiwan University Cancer Center, National Taiwan University College of Medicine, Taipei 106, Taiwan.
| | - Chung-Wu Lin
- Department of Pathology, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei 100, Taiwan.
| | - Ping-Ning Hsu
- Department of Internal Medicine, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei 100, Taiwan.
| | - Li-Tzong Chen
- National Institute of Cancer Research, National Health Research Institutes, Tainan 704, Taiwan.
- Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung 807, Taiwan.
- Department of Internal Medicine, National Cheng-Kung University Hospital, Tainan 704, Taiwan.
| | - Ann-Lii Cheng
- Cancer Research Center, National Taiwan University College of Medicine, Taipei 100, Taiwan.
- Graduate Institute of Oncology, National Taiwan University College of Medicine, Taipei 100, Taiwan.
- National Taiwan University Cancer Center, National Taiwan University College of Medicine, Taipei 106, Taiwan.
- Department of Internal Medicine, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei 100, Taiwan.
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44
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Sun H, Sun C, Xiao W, Sun R. Tissue-resident lymphocytes: from adaptive to innate immunity. Cell Mol Immunol 2019; 16:205-215. [PMID: 30635650 DOI: 10.1038/s41423-018-0192-y] [Citation(s) in RCA: 101] [Impact Index Per Article: 16.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2018] [Revised: 11/26/2018] [Accepted: 11/26/2018] [Indexed: 12/11/2022] Open
Abstract
Efficient immune responses against invading pathogens often involve coordination between cells from both the innate and adaptive immune systems. For multiple decades, it has been believed that CD8+ memory T cells and natural killer (NK) cells constantly and uniformly recirculate. Only recently was the existence of noncirculating memory T and NK cells that remain resident in the peripheral tissues, termed tissue-resident memory T (TRM) cells and tissue-resident NK (trNK) cells, observed in various organs owing to improved techniques. TRM cells populate a wide range of peripheral organs, including the skin, sensory ganglia, gut, lungs, brain, salivary glands, female reproductive tract, and others. Recent findings have demonstrated the existence of TRM in the secondary lymphoid organs (SLOs) as well, leading to revision of the classic theory that they exist only in peripheral organs. trNK cells have been identified in the uterus, skin, kidney, adipose tissue, and salivary glands. These tissue-resident lymphocytes do not recirculate in the blood or lymphatic system and often adopt a unique phenotype that is distinct from those of circulating immune cells. In this review, we will discuss the recent findings on the tissue residency of both innate and adaptive lymphocytes, with a particular focus on CD8+ memory T cells, and describe some advances regarding unconventional T cells (invariant NKT cells, mucosal-associated invariant T cells (MAIT), and γδ T cells) and the emerging family of trNK cells. Specifically, we will focus on the phenotypes and functions of these subsets and discuss their implications in anti-viral and anti-tumor immunity.
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Affiliation(s)
- Haoyu Sun
- Division of Molecular Medicine, Hefei National Laboratory for Physical Sciences at Microscale, the CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Life Sciences, University of Science and Technology of China, Hefei, China. .,Institute of Immunology, University of Science and Technology of China, Hefei, China.
| | - Cheng Sun
- Division of Molecular Medicine, Hefei National Laboratory for Physical Sciences at Microscale, the CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Life Sciences, University of Science and Technology of China, Hefei, China.,Institute of Immunology, University of Science and Technology of China, Hefei, China
| | - Weihua Xiao
- Division of Molecular Medicine, Hefei National Laboratory for Physical Sciences at Microscale, the CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Life Sciences, University of Science and Technology of China, Hefei, China.,Institute of Immunology, University of Science and Technology of China, Hefei, China
| | - Rui Sun
- Division of Molecular Medicine, Hefei National Laboratory for Physical Sciences at Microscale, the CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Life Sciences, University of Science and Technology of China, Hefei, China.,Institute of Immunology, University of Science and Technology of China, Hefei, China
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45
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Germain RN, Huang Y. ILC2s - resident lymphocytes pre-adapted to a specific tissue or migratory effectors that adapt to where they move? Curr Opin Immunol 2018; 56:76-81. [PMID: 30472437 DOI: 10.1016/j.coi.2018.11.001] [Citation(s) in RCA: 31] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2018] [Revised: 10/03/2018] [Accepted: 11/06/2018] [Indexed: 01/08/2023]
Abstract
A cardinal feature of the T-cell adaptive immune system is the antigen-dependent activation of naïve T cells in secondary lymphoid sites, followed by the migration of the resultant effector cells through the efferent lymph to the blood and then into a peripheral tissue site of infection or tumor growth. In contrast, the current view of innate lymphocytes (ILCs), the innate counterparts of T cells, is that they are tissue-resident cells, adapted to their specific environments during development and performing their effector functions locally upon cytokine stimulation. Here we present recent findings that challenge the latter as defining the properties of ILCs, at least ILC2s. Our studies show that IL-25, administrated experimentally or generated in response to helminth infection, triggers local proliferation and activation of intestinal ILC2s that are the precursors to inflammatory ILC2 (iILC2) cells. These cells downregulate CD69 expression, upregulate S1P receptors and move across the villus lymphatic endothelium in an S1P-depndent manner. They subsequently enter the blood stream, through which they traffic to distant organs such as the liver and lung. In the lung, these iILC2 cells play a crucial role in host defense during the pulmonary stage of helminth infection. In the later stage of infection, a fraction of the iILC2 cells phenotypically convert into lung-resident natural ILC2 (nILC2)-like cells while another fraction homes back to their original location in the small intestine. These data support the view that ILC2s possess properties considered characteristic of adaptive T lymphocytes, namely local activation and distant effector function, but in response to alarm cytokines instead of specific antigen. These findings also raise questions about whether other ILC subsets show similar trafficking potential when suitably challenged, the extent to which such cells show plasticity in adapting to new tissue environments beyond the course of early development, and the relative roles of organ-resident versus migratory ILCs in host defense.
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Affiliation(s)
- Ronald N Germain
- Laboratory of Immune System Biology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.
| | - Yuefeng Huang
- Laboratory of Immune System Biology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.
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46
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van Wilgenburg B, Loh L, Chen Z, Pediongco TJ, Wang H, Shi M, Zhao Z, Koutsakos M, Nüssing S, Sant S, Wang Z, D'Souza C, Jia X, Almeida CF, Kostenko L, Eckle SBG, Meehan BS, Kallies A, Godfrey DI, Reading PC, Corbett AJ, McCluskey J, Klenerman P, Kedzierska K, Hinks TSC. MAIT cells contribute to protection against lethal influenza infection in vivo. Nat Commun 2018; 9:4706. [PMID: 30413689 PMCID: PMC6226485 DOI: 10.1038/s41467-018-07207-9] [Citation(s) in RCA: 147] [Impact Index Per Article: 21.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2018] [Accepted: 10/16/2018] [Indexed: 01/28/2023] Open
Abstract
Mucosal associated invariant T (MAIT) cells are evolutionarily-conserved, innate-like lymphocytes which are abundant in human lungs and can contribute to protection against pulmonary bacterial infection. MAIT cells are also activated during human viral infections, yet it remains unknown whether MAIT cells play a significant protective or even detrimental role during viral infections in vivo. Using murine experimental challenge with two strains of influenza A virus, we show that MAIT cells accumulate and are activated early in infection, with upregulation of CD25, CD69 and Granzyme B, peaking at 5 days post-infection. Activation is modulated via cytokines independently of MR1. MAIT cell-deficient MR1-/- mice show enhanced weight loss and mortality to severe (H1N1) influenza. This is ameliorated by prior adoptive transfer of pulmonary MAIT cells in both immunocompetent and immunodeficient RAG2-/-γC-/- mice. Thus, MAIT cells contribute to protection during respiratory viral infections, and constitute a potential target for therapeutic manipulation.
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Affiliation(s)
- Bonnie van Wilgenburg
- Department of Microbiology and Immunology, The Peter Doherty Institute for Infection and Immunity, The University of Melbourne, Parkville, VIC, 3000, Australia
- Peter Medawar Building for Pathogen Research and Translational Gastroenterology Unit, Nuffield Department of Clinical Medicine, University of Oxford, Oxford, OX3 3SY, UK
| | - Liyen Loh
- Department of Microbiology and Immunology, The Peter Doherty Institute for Infection and Immunity, The University of Melbourne, Parkville, VIC, 3000, Australia
| | - Zhenjun Chen
- Department of Microbiology and Immunology, The Peter Doherty Institute for Infection and Immunity, The University of Melbourne, Parkville, VIC, 3000, Australia
| | - Troi J Pediongco
- Department of Microbiology and Immunology, The Peter Doherty Institute for Infection and Immunity, The University of Melbourne, Parkville, VIC, 3000, Australia
| | - Huimeng Wang
- Department of Microbiology and Immunology, The Peter Doherty Institute for Infection and Immunity, The University of Melbourne, Parkville, VIC, 3000, Australia
| | - Mai Shi
- Department of Microbiology and Immunology, The Peter Doherty Institute for Infection and Immunity, The University of Melbourne, Parkville, VIC, 3000, Australia
| | - Zhe Zhao
- Department of Microbiology and Immunology, The Peter Doherty Institute for Infection and Immunity, The University of Melbourne, Parkville, VIC, 3000, Australia
| | - Marios Koutsakos
- Department of Microbiology and Immunology, The Peter Doherty Institute for Infection and Immunity, The University of Melbourne, Parkville, VIC, 3000, Australia
| | - Simone Nüssing
- Department of Microbiology and Immunology, The Peter Doherty Institute for Infection and Immunity, The University of Melbourne, Parkville, VIC, 3000, Australia
| | - Sneha Sant
- Department of Microbiology and Immunology, The Peter Doherty Institute for Infection and Immunity, The University of Melbourne, Parkville, VIC, 3000, Australia
| | - Zhongfang Wang
- Department of Microbiology and Immunology, The Peter Doherty Institute for Infection and Immunity, The University of Melbourne, Parkville, VIC, 3000, Australia
| | - Criselle D'Souza
- Department of Microbiology and Immunology, The Peter Doherty Institute for Infection and Immunity, The University of Melbourne, Parkville, VIC, 3000, Australia
| | - Xiaoxiao Jia
- Department of Microbiology and Immunology, The Peter Doherty Institute for Infection and Immunity, The University of Melbourne, Parkville, VIC, 3000, Australia
| | - Catarina F Almeida
- Department of Microbiology and Immunology, The Peter Doherty Institute for Infection and Immunity, The University of Melbourne, Parkville, VIC, 3000, Australia
- ARC Centre of Excellence in Advanced Molecular Imaging, The University of Melbourne, Parkville, VIC, 3010, Australia
| | - Lyudmila Kostenko
- Department of Microbiology and Immunology, The Peter Doherty Institute for Infection and Immunity, The University of Melbourne, Parkville, VIC, 3000, Australia
| | - Sidonia B G Eckle
- Department of Microbiology and Immunology, The Peter Doherty Institute for Infection and Immunity, The University of Melbourne, Parkville, VIC, 3000, Australia
| | - Bronwyn S Meehan
- Department of Microbiology and Immunology, The Peter Doherty Institute for Infection and Immunity, The University of Melbourne, Parkville, VIC, 3000, Australia
| | - Axel Kallies
- Department of Microbiology and Immunology, The Peter Doherty Institute for Infection and Immunity, The University of Melbourne, Parkville, VIC, 3000, Australia
| | - Dale I Godfrey
- Department of Microbiology and Immunology, The Peter Doherty Institute for Infection and Immunity, The University of Melbourne, Parkville, VIC, 3000, Australia
- ARC Centre of Excellence in Advanced Molecular Imaging, The University of Melbourne, Parkville, VIC, 3010, Australia
| | - Patrick C Reading
- Department of Microbiology and Immunology, The Peter Doherty Institute for Infection and Immunity, The University of Melbourne, Parkville, VIC, 3000, Australia
| | - Alexandra J Corbett
- Department of Microbiology and Immunology, The Peter Doherty Institute for Infection and Immunity, The University of Melbourne, Parkville, VIC, 3000, Australia
| | - James McCluskey
- Department of Microbiology and Immunology, The Peter Doherty Institute for Infection and Immunity, The University of Melbourne, Parkville, VIC, 3000, Australia
| | - Paul Klenerman
- Peter Medawar Building for Pathogen Research and Translational Gastroenterology Unit, Nuffield Department of Clinical Medicine, University of Oxford, Oxford, OX3 3SY, UK.
| | - Katherine Kedzierska
- Department of Microbiology and Immunology, The Peter Doherty Institute for Infection and Immunity, The University of Melbourne, Parkville, VIC, 3000, Australia
| | - Timothy S C Hinks
- Department of Microbiology and Immunology, The Peter Doherty Institute for Infection and Immunity, The University of Melbourne, Parkville, VIC, 3000, Australia
- Respiratory Medicine Unit, Nuffield Department of Medicine, Experimental Medicine Division, University of Oxford, Oxford, OX3 9DU, UK
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47
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Low mucosal-associated invariant T-cell number in peripheral blood of patients with immune thrombocytopenia and their response to prednisolone. PLoS One 2018; 13:e0207149. [PMID: 30408105 PMCID: PMC6224073 DOI: 10.1371/journal.pone.0207149] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2018] [Accepted: 10/25/2018] [Indexed: 12/23/2022] Open
Abstract
Mucosal-associated invariant T (MAIT) cells help protect against certain infections and are related to some autoimmune diseases. Immune thrombocytopenia (ITP) is a relatively rare hematological autoimmune disease associated with low platelet count. We designed a cross-sectional study wherein we examined peripheral blood samples of patients with ITP for the number of MAIT cells (CD3+TCR-Vα7.2+CD161+IL-18Rα+ lymphocytes) and their CD4/8 subsets (by flow cytometry) and levels of cytokines (by multiplex assays). The study cohort included 18 patients with ITP and 20 healthy controls (HCs). We first compared the number of MAIT cells between HCs and patients with ITP and then performed subgroup analysis in patients with ITP. The number of total MAIT cells in patients with ITP was significantly lower than that in HCs (p < 0.0001), and the CD4-CD8+ subset of MAIT cells showed the same trend. Moreover, patients with ITP refractory to prednisolone exhibited a significantly lower number of total MAIT and CD4-CD8+ MAIT cells than patients sensitive to prednisolone. The number of total MAIT and CD4-CD8+ MAIT cells was not correlated with the response to thrombopoietin receptor agonist treatment or with Helicobacter pylori infection. We found no relation between cytokine levels and response to prednisolone treatment, although the levels of IP-10 and RANTES showed a correlation with the number of total MAIT and CD4-CD8+ MAIT cells. In conclusion, total MAIT and CD4-CD8+ MAIT cells in peripheral blood were decreased in patients with ITP, correlating with their response to prednisolone.
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48
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D’Souza C, Chen Z, Corbett AJ. Revealing the protective and pathogenic potential of MAIT cells. Mol Immunol 2018; 103:46-54. [DOI: 10.1016/j.molimm.2018.08.022] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2018] [Accepted: 08/22/2018] [Indexed: 12/13/2022]
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49
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Barathan M, Mohamed R, Yong YK, Kannan M, Vadivelu J, Saeidi A, Larsson M, Shankar EM. Viral Persistence and Chronicity in Hepatitis C Virus Infection: Role of T-Cell Apoptosis, Senescence and Exhaustion. Cells 2018; 7:cells7100165. [PMID: 30322028 PMCID: PMC6210370 DOI: 10.3390/cells7100165] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2018] [Revised: 10/02/2018] [Accepted: 10/09/2018] [Indexed: 02/06/2023] Open
Abstract
Hepatitis C virus (HCV) represents a challenging global health threat to ~200 million infected individuals. Clinical data suggest that only ~10–15% of acutely HCV-infected individuals will achieve spontaneous viral clearance despite exuberant virus-specific immune responses, which is largely attributed to difficulties in recognizing the pathognomonic symptoms during the initial stages of exposure to the virus. Given the paucity of a suitable small animal model, it is also equally challenging to study the early phases of viral establishment. Further, the host factors contributing to HCV chronicity in a vast majority of acutely HCV-infected individuals largely remain unexplored. The last few years have witnessed a surge in studies showing that HCV adopts myriad mechanisms to disconcert virus-specific immune responses in the host to establish persistence, which includes, but is not limited to viral escape mutations, viral growth at privileged sites, and antagonism. Here we discuss a few hitherto poorly explained mechanisms employed by HCV that are believed to lead to chronicity in infected individuals. A better understanding of these mechanisms would aid the design of improved therapeutic targets against viral establishment in susceptible individuals.
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Affiliation(s)
- Muttiah Barathan
- Department of Medical Microbiology, Faculty of Medicine, University of Malaya, LembahPantai, 50603 Kuala Lumpur, Malaysia.
| | - Rosmawati Mohamed
- Department of Medicine, Faculty of Medicine, University of Malaya, 50603 LembahPantai, Kuala Lumpur, Malaysia.
| | - Yean K Yong
- Laboratory Center, Xiamen University Malaysia, 43900 Sepang, Malaysia.
| | - Meganathan Kannan
- Division of Blood and Vascular Biology, Department of Life Sciences, Central University of Tamil Nadu (CUTN), Thiruvarur 610005, India.
| | - Jamuna Vadivelu
- Department of Medical Microbiology, Faculty of Medicine, University of Malaya, LembahPantai, 50603 Kuala Lumpur, Malaysia.
| | - Alireza Saeidi
- Department of Medical Microbiology, Faculty of Medicine, University of Malaya, LembahPantai, 50603 Kuala Lumpur, Malaysia.
| | - Marie Larsson
- Division of Molecular Virology, Department of Clinical and Experimental Medicine, Linkoping University, 58 183 Linkoping, Sweden.
| | - Esaki Muthu Shankar
- Division of Infection Biology and Medical Microbiology, Department of Life Sciences, Central University of Tamil Nadu (CUTN), Thiruvarur 610005, India.
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50
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Sharma A, Lawry SM, Klein BS, Wang X, Sherer NM, Zumwalde NA, Gumperz JE. LFA-1 Ligation by High-Density ICAM-1 Is Sufficient To Activate IFN-γ Release by Innate T Lymphocytes. THE JOURNAL OF IMMUNOLOGY 2018; 201:2452-2461. [PMID: 30171164 DOI: 10.4049/jimmunol.1800537] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/16/2018] [Accepted: 08/16/2018] [Indexed: 11/19/2022]
Abstract
By binding to its ligand ICAM-1, LFA-1 is known to mediate both adhesion and costimulatory signaling for T cell activation. The constitutively high LFA-1 cell surface expression of invariant NKT (iNKT) cells has been shown to be responsible for their distinctive tissue homing and residency within ICAM-rich endothelial vessels. However, the functional impact of LFA-1 on the activation of iNKT cells and other innate T lymphocyte subsets has remained largely unexplored. In particular, it is not clear whether LFA-1 contributes to innate-like pathways of T cell activation, such as IFN-γ secretion in response to IL-12. Using a recombinant ICAM-1-Fc fusion protein to stimulate human iNKT cells in the absence of APCs, we show that LFA-1 engagement enhances their IL-12-driven IFN-γ production. Surprisingly, exposure to high densities of ICAM-1 was also sufficient to activate iNKT cell cytokine secretion independently of IL-12 and associated JAK/STAT signaling. LFA-1 engagement induced elevated cytoplasmic Ca2+ and rapid ERK phosphorylation in iNKT cells, and the resulting IFN-γ secretion was dependent on both of these pathways. Analysis of freshly isolated human PBMC samples revealed that a fraction of lymphocytes that showed elevated LFA-1 cell surface expression produced IFN-γ in response to plate-bound ICAM-1-Fc. A majority of the responding cells were T cells, with the remainder NK cells. The responding T cells included iNKT cells, MAIT cells, and Vδ2+ γδ T cells. These results delineate a novel integrin-mediated pathway of IFN-γ secretion that is a shared feature of innate lymphocytes.
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Affiliation(s)
- Akshat Sharma
- Department of Medical Microbiology and Immunology, University of Wisconsin School of Medicine and Public Health, Madison, WI 53706; and
| | - Stephanie M Lawry
- Department of Medical Microbiology and Immunology, University of Wisconsin School of Medicine and Public Health, Madison, WI 53706; and
| | - Bruce S Klein
- Department of Medical Microbiology and Immunology, University of Wisconsin School of Medicine and Public Health, Madison, WI 53706; and
| | - Xiaohua Wang
- Department of Medical Microbiology and Immunology, University of Wisconsin School of Medicine and Public Health, Madison, WI 53706; and
| | - Nathan M Sherer
- Department of Oncology, University of Wisconsin School of Medicine and Public Health, Madison, WI 53706
| | - Nicholas A Zumwalde
- Department of Medical Microbiology and Immunology, University of Wisconsin School of Medicine and Public Health, Madison, WI 53706; and
| | - Jenny E Gumperz
- Department of Medical Microbiology and Immunology, University of Wisconsin School of Medicine and Public Health, Madison, WI 53706; and
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