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1
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Bilodeau PA, Yeh A, Lechner-Scott J, Hawkes CH, Giovannoni G, Levy M. Potential mechanisms of how B-cell depletion works in MOGAD. Mult Scler Relat Disord 2025; 93:106269. [PMID: 39827742 DOI: 10.1016/j.msard.2025.106269] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/22/2025]
Affiliation(s)
- Philippe A Bilodeau
- Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
| | - Ann Yeh
- Division of Neurology, Department of Pediatrics, The Hospital for Sick Children, University of Toronto, ON, Canada
| | | | - Christopher H Hawkes
- Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK
| | - Gavin Giovannoni
- Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK
| | - Michael Levy
- Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
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2
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Bulgur D, Moura RM, Ribot JC. Key actors in neuropathophysiology: The role of γδ T cells. Eur J Immunol 2024; 54:e2451055. [PMID: 39240039 PMCID: PMC11628923 DOI: 10.1002/eji.202451055] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2024] [Revised: 08/26/2024] [Accepted: 08/27/2024] [Indexed: 09/07/2024]
Abstract
The neuroimmune axis has been the focus of many studies, with special emphasis on the interactions between the central nervous system and the different immune cell subsets. T cells are namely recognized to play a critical role due to their interaction with nerves, by secreting cytokines and neurotrophins, which regulate the development, function, and survival of neurons. In this context, γδ T cells are particularly relevant, as they colonize specific tissues, namely the meninges, and have a wide variety of complex functions that balance physiological systems. Notably, γδ T cells are not only key components for maintaining brain homeostasis but are also responsible for triggering or preventing inflammatory responses in various pathologies, including neurodegenerative diseases as well as neuropsychiatric and developmental disorders. Here, we provide an overview of the current state of the art on the contribution of γδ T cells in neuropathophysiology and delve into the molecular mechanisms behind it. We aim to shed light on γδ T cell functions in the central nervous system while highlighting upcoming challenges in the field and providing new clues for potential therapeutic strategies.
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Affiliation(s)
- Deniz Bulgur
- Instituto de Medicina MolecularFaculdade de Medicina da Universidade de Lisboa Avenida Professor Egas MonizLisbon1649‐028Portugal
| | - Raquel Macedo Moura
- Instituto de Medicina MolecularFaculdade de Medicina da Universidade de Lisboa Avenida Professor Egas MonizLisbon1649‐028Portugal
| | - Julie C. Ribot
- Instituto de Medicina MolecularFaculdade de Medicina da Universidade de Lisboa Avenida Professor Egas MonizLisbon1649‐028Portugal
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3
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Kruse A, Imery I, Corell L, Hjalmarsson E, Fernandez-Gonzalo R, Von Walden F, Reitzner SM. Circulating immune cell populations at rest and in response to acute endurance exercise in young adults with cerebral palsy. Dev Med Child Neurol 2024; 66:902-909. [PMID: 38111130 DOI: 10.1111/dmcn.15835] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/21/2023] [Revised: 11/16/2023] [Accepted: 11/17/2023] [Indexed: 12/20/2023]
Abstract
AIM The aim of this observational study was to determine the immune status and function in young adults with cerebral palsy (CP) in comparison to typically developing individuals. METHOD Blood samples from 12 individuals with CP (five males, seven females; mean age: 25 years 1 month (5 years 9 months); age range: 19-38 years) and 17 typically developing individuals (eight males, nine females; mean age: 31 years 4 months (6 years 2 months); age range: 20-40 years) were collected before, immediately after, and 1 hour after 45 minutes of frame running or running respectively. Independent t-tests were used to compare heart rate, level of exertion, and baseline cell proportions between groups. Mixed model analysis of variance was utilized to investigate immune cell responses to exercise across groups. RESULTS Baseline levels of gamma delta (TCRγδ+) T-cells were significantly higher (absolute percentage: +2.65, p = 0.028) in the individuals with CP. Several cell populations showed similar significant changes after exercise in both CP and typically developing groups. Cytotoxic (CD8+) T-cells were only significantly elevated immediately after exercise in the typically developing participants (p < 0.01). Individuals with CP exhibited significantly lower heart rates (-11.1%, p < 0.01), despite similar ratings of perceived exertion. INTERPRETATION Elevated baseline TCRγδ+ T-cells may indicate low-grade inflammation in adults with CP. Although most of the cell populations showed typical responses to endurance exercise, the absence of response in CD8+ T-cells in individuals with CP may indicate the need for higher intensity during exercise. WHAT THIS PAPER ADDS TCRγδ+ T-cell baseline levels are elevated in adults with cerebral palsy (CP). The CD8+ T-cell response to exercise was blunted in adults with CP. Exercise intensity is decisive for CD8+ T-cell responses in individuals with CP.
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Affiliation(s)
- Annika Kruse
- Department of Women's and Children's Health, Division of Neurology/Pediatric Orthopedics, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden
- Institute of Human Movement Science, Sport and Health, University of Graz, Austria
| | - Ian Imery
- Department of Women's and Children's Health, Division of Neurology/Pediatric Orthopedics, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden
- College of Health and Human Performance, University of Florida, Gainesville, FL, USA
| | - Linnéa Corell
- Department of Women's and Children's Health, Division of Neurology/Pediatric Orthopedics, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden
| | - Emma Hjalmarsson
- Department of Women's and Children's Health, Division of Neurology/Pediatric Orthopedics, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden
- Functional Area Occupational Therapy and Physiotherapy, Karolinska University Hospital, Stockholm, Sweden
| | - Rodrigo Fernandez-Gonzalo
- Department of Laboratory Medicine, Division of Clinical Physiology, Karolinska Institutet, Stockholm, Sweden
- Unit of Clinical Physiology, Karolinska University Hospital, Stockholm, Sweden
| | - Ferdinand Von Walden
- Department of Women's and Children's Health, Division of Neurology/Pediatric Orthopedics, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden
| | - Stefan M Reitzner
- Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden
- Department of Women's and Children's Health, Karolinska Institutet, Stockholm, Sweden
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4
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Lv M, Zhang Z, Cui Y. Unconventional T cells in brain homeostasis, injury and neurodegeneration. Front Immunol 2023; 14:1273459. [PMID: 37854609 PMCID: PMC10579804 DOI: 10.3389/fimmu.2023.1273459] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2023] [Accepted: 09/20/2023] [Indexed: 10/20/2023] Open
Abstract
The interaction between peripheral immune cells and the brain is an important component of the neuroimmune axis. Unconventional T cells, which include natural killer T (NKT) cells, mucosal-associated invariant T (MAIT) cells, γδ T cells, and other poorly defined subsets, are a special group of T lymphocytes that recognize a wide range of nonpolymorphic ligands and are the connection between adaptive and innate immunity. Recently, an increasing number of complex functions of these unconventional T cells in brain homeostasis and various brain disorders have been revealed. In this review, we describe the classification and effector function of unconventional T cells, review the evidence for the involvement of unconventional T cells in the regulation of brain homeostasis, summarize the roles and mechanisms of unconventional T cells in the regulation of brain injury and neurodegeneration, and discuss immunotherapeutic potential as well as future research goals. Insight of these processes can shed light on the regulation of T cell immunity on brain homeostasis and diseases and provide new clues for therapeutic approaches targeting brain injury and neurodegeneration.
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Affiliation(s)
- Mengfei Lv
- Institute of Neuroregeneration and Neurorehabilitation, Qingdao University, Qingdao, Shandong, China
- Qingdao Medical College, Qingdao University, Qingdao, China
| | - Zhaolong Zhang
- Department of Interventional Radiology, The Affiliated Hospital of Qingdao University, Qingdao, Shandong, China
| | - Yu Cui
- Institute of Neuroregeneration and Neurorehabilitation, Qingdao University, Qingdao, Shandong, China
- Qingdao Medical College, Qingdao University, Qingdao, China
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5
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Wang C, Zhou Y, Feinstein A. Neuro-immune crosstalk in depressive symptoms of multiple sclerosis. Neurobiol Dis 2023; 177:106005. [PMID: 36680805 DOI: 10.1016/j.nbd.2023.106005] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2022] [Revised: 01/10/2023] [Accepted: 01/17/2023] [Indexed: 01/20/2023] Open
Abstract
Depressive disorders can occur in up to 50% of people with multiple sclerosis in their lifetime. If left untreated, comorbid major depressive disorders may not spontaneously remit and is associated with an increased morbidity and mortality. Conversely, epidemiological evidence supports increased psychiatric visit as a significant prodromal event prior to diagnosis of MS. Are there common molecular pathways that contribute to the co-development of MS and psychiatric illnesses? We discuss immune cells that are dysregulated in MS and how such dysregulation can induce or protect against depressive symptoms. This is not meant to be a comprehensive review of all molecular pathways but rather a framework to guide future investigations of immune responses in depressed versus euthymic people with MS. Currently, there is weak evidence supporting the use of antidepressant medication in comorbid MS patients. It is our hope that by better understanding the neuroimmune crosstalk in the context of depression in MS, we can enhance the potential for future therapeutic options.
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Affiliation(s)
- Chao Wang
- Biological Sciences Platform, Sunnybrook Research Institute, Toronto, ON, Canada; Department of Immunology, University of Toronto, Toronto, ON, Canada
| | - Yulin Zhou
- Biological Sciences Platform, Sunnybrook Research Institute, Toronto, ON, Canada; Department of Immunology, University of Toronto, Toronto, ON, Canada
| | - Anthony Feinstein
- Department of Psychiatry, Sunnybrook Health Sciences Centre and University of Toronto, Toronto, ON, Canada.
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6
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Sun D, Chan N, Shao H, Born WK, Kaplan HJ. γδ T Cells Activated in Different Inflammatory Environments Are Functionally Distinct. JOURNAL OF IMMUNOLOGY (BALTIMORE, MD. : 1950) 2022; 208:1224-1231. [PMID: 35101894 DOI: 10.4049/jimmunol.2100967] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/06/2021] [Accepted: 12/17/2021] [Indexed: 12/15/2022]
Abstract
γδ T cells are important immunoregulatory cells in experimental autoimmune uveitis (EAU), and the activation status of γδ T cells determines their disease-enhancing or inhibitory effects. Because γδ T cells can be activated via various pathways, we questioned whether the nature of their activation might impact their function. In this study, we show that γδ T cells activated under different inflammatory conditions differ greatly in their functions. Whereas anti-CD3 treatment activated both IFN-γ+ and IL-17+ γδ T cells, cytokines preferentially activated IL-17+ γδ T cells. γδ T cells continued to express high levels of surface CD73 after exposure to inflammatory cytokines, but they downregulated surface CD73 after exposure to dendritic cells. Although both CD73high and CD73low cells have a disease-enhancing effect, the CD73low γδ T cells are less inhibitory. We also show that polarized activation not only applies to αβ T cells and myeloid cells, but also to γδ T cells. After activation under Th17-polarizing conditions, γδ T cells predominantly expressed IL-17 (gdT17), but after activation under Th1 polarizing conditions (gdT1) they mainly expressed IFN-γ. The pro-Th17 activity of γδ T cells was associated with gdT17, but not gdT1. Our results demonstrate that the functional activity of γδ T cells is strikingly modulated by their activation level, as well as the pathway through which they were activated.
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Affiliation(s)
- Deming Sun
- Doheny Eye Institute, Department of Ophthalmology, David Geffen School of Medicine at UCLA, Los Angeles, CA;
| | - Nymph Chan
- Doheny Eye Institute, Department of Ophthalmology, David Geffen School of Medicine at UCLA, Los Angeles, CA
| | - Hui Shao
- Department of Ophthalmology and Visual Sciences, Kentucky Lions Eye Center, University of Louisville, Louisville, KY
| | - Willi K Born
- Department of Biomedical Research, National Jewish Health Center, Denver, CO; and
| | - Henry J Kaplan
- School of Medicine, Saint Louis University, St. Louis, MO
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7
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Ruder J, Rex J, Obahor S, Docampo MJ, Müller AMS, Schanz U, Jelcic I, Martin R. NK Cells and Innate-Like T Cells After Autologous Hematopoietic Stem Cell Transplantation in Multiple Sclerosis. Front Immunol 2022; 12:794077. [PMID: 34975899 PMCID: PMC8716406 DOI: 10.3389/fimmu.2021.794077] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2021] [Accepted: 11/29/2021] [Indexed: 01/18/2023] Open
Abstract
Multiple sclerosis (MS) is an autoimmune disease of the central nervous system, in which autoreactive T and B cells play important roles. Other lymphocytes such as NK cells and innate-like T cells appear to be involved as well. To name a few examples, CD56bright NK cells were described as an immunoregulatory NK cell subset in MS while innate-like T cells in MS were described in brain lesions and with proinflammatory signatures. Autologous hematopoietic stem cell transplantation (aHSCT) is a procedure used to treat MS. This procedure includes hematopoietic stem/progenitor cell (HSPC) mobilization, then high-dose chemotherapy combined with anti-thymocyte globulin (ATG) and subsequent infusion of the patients own HSPCs to reconstitute a functional immune system. aHSCT inhibits MS disease activity very effectively and for long time, presumably due to elimination of autoreactive T cells. Here, we performed multidimensional flow cytometry experiments in peripheral blood lymphocytes of 27 MS patients before and after aHSCT to address its potential influence on NK and innate-like T cells. After aHSCT, the relative frequency and absolute numbers of CD56bright NK cells rise above pre-aHSCT levels while all studied innate-like T cell populations decrease. Hence, our data support an enhanced immune regulation by CD56bright NK cells and the efficient reduction of proinflammatory innate-like T cells by aHSCT in MS. These observations contribute to our current understanding of the immunological effects of aHSCT in MS.
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Affiliation(s)
- Josefine Ruder
- Neuroimmunology and Multiple Sclerosis (MS) Research Section (NIMS), Department of Neurology, University and University Hospital Zurich, Zurich, Switzerland
| | - Jordan Rex
- Neuroimmunology and Multiple Sclerosis (MS) Research Section (NIMS), Department of Neurology, University and University Hospital Zurich, Zurich, Switzerland
| | - Simon Obahor
- Neuroimmunology and Multiple Sclerosis (MS) Research Section (NIMS), Department of Neurology, University and University Hospital Zurich, Zurich, Switzerland
| | - María José Docampo
- Neuroimmunology and Multiple Sclerosis (MS) Research Section (NIMS), Department of Neurology, University and University Hospital Zurich, Zurich, Switzerland
| | - Antonia M S Müller
- Department of Medical Oncology and Hematology, University and University Hospital Zurich, Zurich, Switzerland
| | - Urs Schanz
- Department of Medical Oncology and Hematology, University and University Hospital Zurich, Zurich, Switzerland
| | - Ilijas Jelcic
- Neuroimmunology and Multiple Sclerosis (MS) Research Section (NIMS), Department of Neurology, University and University Hospital Zurich, Zurich, Switzerland
| | - Roland Martin
- Neuroimmunology and Multiple Sclerosis (MS) Research Section (NIMS), Department of Neurology, University and University Hospital Zurich, Zurich, Switzerland
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8
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Ryan L, Mills KHG. Sex differences regulate immune responses in experimental autoimmune encephalomyelitis and multiple sclerosis. Eur J Immunol 2021; 52:24-33. [PMID: 34727577 DOI: 10.1002/eji.202149589] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2021] [Revised: 09/30/2021] [Accepted: 10/29/2021] [Indexed: 12/26/2022]
Abstract
MS is an autoimmune disease of the CNS that afflicts over 2.5 million people worldwide. There are striking sex differences in the susceptibility to and progression of this disease in humans. Females are twice as likely to develop MS than males, whereas disease progression and disability is more rapid in males compared with females; however, the latter is still controversial. There is growing evidence, mainly from animal models, that innate and adaptive immune responses are different in males and females, and that this can influence the outcome of a range of diseases including infection, cancer, and autoimmunity. Since MS is an immune-mediated disease, sex differences in pathogenic immune responses may account for some of the differences in susceptibility to and progression seen in men versus women. Indeed, data from the mouse model of MS, EAE, have already provided some evidence that female mice have earlier disease onset associated with stronger Th17 responses. This review will discuss the possible immunological basis of sex differences in susceptibility and disease outcome in EAE and MS and how a better understanding of sex differences in the responses to disease-modifying therapies may lead to improved patient treatment.
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Affiliation(s)
- Lucy Ryan
- School of Biochemistry and Immunology, Trinity Biomedical Science Institute, Trinity College Dublin, Dublin 2, Ireland
| | - Kingston H G Mills
- School of Biochemistry and Immunology, Trinity Biomedical Science Institute, Trinity College Dublin, Dublin 2, Ireland
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9
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Interleukin 17A Derived from γδ T Cell Induces Demyelination of the Brain in Angiostrongylus cantonensis Infection. Mol Neurobiol 2021; 58:3968-3982. [PMID: 33904019 DOI: 10.1007/s12035-021-02366-1] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/01/2021] [Accepted: 03/19/2021] [Indexed: 10/21/2022]
Abstract
Angiostrongylus cantonensis infection is a typical cause of eosinophilic encephalitis (EM), which has been reported to induce serious damage in the central nervous system. Both parasite and host factors contribute to the onset of EM, but the related immune-inflammation pathogenesis remains poorly characterised. An A. cantonensis infection model was generated through the infection of mice by gavage. Transmission electron microscopy and immunohistochemistry were used to assess the pathologic changes in the brain. The mRNA expression of inflammatory factors was tested using qRT-PCR. A combination of flow cytometry and western blotting was used to evaluate the alteration of leukocytes and related cytokines. A critical role of IL-17 was found by injecting IL-17A monoclonal antibody into naïve and A. cantonensis-infected mice. A. cantonensis larvae altered the immune homeostasis in the brain, leading to the destruction of myelin sheaths and activation of microglia and macrophage. During this process, IL-17A accumulation was observed, and IL-17RA was expressed in oligodendrocytes and microglia during the infection. Notably, γδ T cell was the major origin of IL-17A production induced by the parasite. After an IL-17A-neutralising antibody was applied, alterations in myelination and the state of the microglia/macrophage were discovered; the neurobehavioural scores of the mice also improved. Our study reveals one unrecognised impact of the γδ T cells in parasitic encephalopathy and emphasises that blocking IL-17A signalling can attenuate microglia and macrophage activation, thus reducing CNS demyelination and ameliorating the neurobehavioural deficit in A. cantonensis-infected mice.
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10
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Edwards SC, Sutton CE, Ladell K, Grant EJ, McLaren JE, Roche F, Dash P, Apiwattanakul N, Awad W, Miners KL, Lalor SJ, Ribot JC, Baik S, Moran B, McGinley A, Pivorunas V, Dowding L, Macoritto M, Paez-Cortez J, Slavin A, Anderson G, Silva-Santos B, Hokamp K, Price DA, Thomas PG, McLoughlin RM, Mills KHG. A population of proinflammatory T cells coexpresses αβ and γδ T cell receptors in mice and humans. J Exp Med 2020; 217:133848. [PMID: 32106283 PMCID: PMC7201916 DOI: 10.1084/jem.20190834] [Citation(s) in RCA: 29] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2019] [Revised: 11/29/2019] [Accepted: 01/17/2020] [Indexed: 12/18/2022] Open
Abstract
T cells are classically recognized as distinct subsets that express αβ or γδ TCRs. We identify a novel population of T cells that coexpress αβ and γδ TCRs in mice and humans. These hybrid αβ-γδ T cells arose in the murine fetal thymus by day 16 of ontogeny, underwent αβ TCR-mediated positive selection into CD4+ or CD8+ thymocytes, and constituted up to 10% of TCRδ+ cells in lymphoid organs. They expressed high levels of IL-1R1 and IL-23R and secreted IFN-γ, IL-17, and GM-CSF in response to canonically restricted peptide antigens or stimulation with IL-1β and IL-23. Hybrid αβ-γδ T cells were transcriptomically distinct from conventional γδ T cells and displayed a hyperinflammatory phenotype enriched for chemokine receptors and homing molecules that facilitate migration to sites of inflammation. These proinflammatory T cells promoted bacterial clearance after infection with Staphylococcus aureus and, by licensing encephalitogenic Th17 cells, played a key role in the development of autoimmune disease in the central nervous system.
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Affiliation(s)
- Sarah C Edwards
- Immune Regulation Research Group, School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin, Ireland
| | - Caroline E Sutton
- Immune Regulation Research Group, School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin, Ireland
| | - Kristin Ladell
- Division of Infection and Immunity, Cardiff University School of Medicine, Heath Park, Cardiff, UK
| | - Emma J Grant
- Division of Infection and Immunity, Cardiff University School of Medicine, Heath Park, Cardiff, UK.,Infection and Immunity Program and Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Clayton, Victoria, Australia
| | - James E McLaren
- Division of Infection and Immunity, Cardiff University School of Medicine, Heath Park, Cardiff, UK
| | - Fiona Roche
- Smurfit Institute of Genetics, Trinity College Dublin, Dublin, Ireland
| | - Pradyot Dash
- Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN
| | - Nopporn Apiwattanakul
- Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN.,Division of Infectious Diseases, Department of Pediatrics, Faculty of Medicine, Ramathibodi Hospital, Mahidol University, Bangkok, Thailand
| | - Walid Awad
- Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN
| | - Kelly L Miners
- Division of Infection and Immunity, Cardiff University School of Medicine, Heath Park, Cardiff, UK
| | - Stephen J Lalor
- Host Pathogen Interactions Group, School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin, Ireland
| | - Julie C Ribot
- Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, Lisboa, Portugal
| | - Song Baik
- Institute of Immunology and Immunotherapy, College of Medical and Dental Sciences, Medical School, University of Birmingham, Edgbaston, Birmingham, UK
| | - Barry Moran
- Immune Regulation Research Group, School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin, Ireland
| | - Aoife McGinley
- Immune Regulation Research Group, School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin, Ireland
| | | | | | | | | | | | - Graham Anderson
- Institute of Immunology and Immunotherapy, College of Medical and Dental Sciences, Medical School, University of Birmingham, Edgbaston, Birmingham, UK
| | - Bruno Silva-Santos
- Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, Lisboa, Portugal
| | - Karsten Hokamp
- Smurfit Institute of Genetics, Trinity College Dublin, Dublin, Ireland
| | - David A Price
- Division of Infection and Immunity, Cardiff University School of Medicine, Heath Park, Cardiff, UK
| | - Paul G Thomas
- Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN
| | - Rachel M McLoughlin
- Host Pathogen Interactions Group, School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin, Ireland
| | - Kingston H G Mills
- Immune Regulation Research Group, School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin, Ireland
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11
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Wo J, Zhang F, Li Z, Sun C, Zhang W, Sun G. The Role of Gamma-Delta T Cells in Diseases of the Central Nervous System. Front Immunol 2020; 11:580304. [PMID: 33193380 PMCID: PMC7644879 DOI: 10.3389/fimmu.2020.580304] [Citation(s) in RCA: 47] [Impact Index Per Article: 9.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2020] [Accepted: 09/30/2020] [Indexed: 01/08/2023] Open
Abstract
Gamma-delta (γδ) T cells are a subset of T cells that promote the inflammatory responses of lymphoid and myeloid lineages, and are especially vital to the initial inflammatory and immune responses. Given the capability to connect crux inflammations of adaptive and innate immunity, γδ T cells are responsive to multiple molecular cues and can acquire the capacity to induce various cytokines, such as GM-CSF, IL-4, IL-17, IL-21, IL-22, and IFN-γ. Nevertheless, the exact mechanisms responsible for γδ T cell proinflammatory functions remain poorly understood, particularly in the context of the central nervous system (CNS) diseases. CNS disease, usually leading to irreversible cognitive and physical disability, is becoming a worldwide public health problem. Here, we offer a review of the neuro-inflammatory and immune functions of γδ T cells, intending to understand their roles in CNS diseases, which may be crucial for the development of novel clinical applications.
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Affiliation(s)
- Jin Wo
- Department of Orthopedics, First Affiliated Hospital, Jinan University, Guangzhou, China
| | - Feng Zhang
- Intensive Care Unit, First Affiliated Hospital, Jinan University, Guangzhou, China
| | - Zhizhong Li
- Department of Orthopedics, First Affiliated Hospital, Jinan University, Guangzhou, China
| | - Chenghong Sun
- State Key Laboratory of Generic Manufacture Technology of Chinese Traditional Medicine, Linyi, China
| | - Wencai Zhang
- Department of Orthopedics, First Affiliated Hospital, Jinan University, Guangzhou, China
| | - Guodong Sun
- Department of Orthopedics, First Affiliated Hospital, Jinan University, Guangzhou, China
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12
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Li T, Zhou Y, Sun X, Bian Y, Wang K, Guo Q, Wang Q, Qiu F. Interleukin-2 maintains the survival of interleukin-17 + gamma/delta T cells in inflammation and autoimmune diseases. Int Immunopharmacol 2020; 86:106721. [PMID: 32615450 DOI: 10.1016/j.intimp.2020.106721] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2020] [Revised: 06/15/2020] [Accepted: 06/15/2020] [Indexed: 10/24/2022]
Abstract
There is increasing appreciation of the critical pathogenic role of IL-17 in inflammation and autoimmune diseases, which could be produced from both adaptive Th17 cells and innate γδ T cells. Existing evidences suggest that IL-2 is important for in vivo accumulation of IL-17+ γδ T cells, leaving the mechanisms still elusive. Herein, using lupus-prone MRL/lpr mice, we demonstrated that splenic γδ T cells were potent IL-17 producers at the onset of lupus, which could be diminished by in vivo IL-2 neutralization. Additional in vivo results showed that neutralization of IL-2 also significantly deleted the IL-17-producing γδ T cells in ovalbumin (OVA) /CFA-immunized B6 mice. Using splenic γδ T cells from OVA/CFA-immunized B6 mice, we further demonstrated that IL-2 could induce IL-17 production alone or together with IL-1β or IL-23 or anti-TCRγδ. Mechanism studies demonstrated that IL-2 could support the survival of γδ T cells, rather than induce the proliferation. Through specific pharmacologic inhibitor, we demonstrated that IL-2 could maintain that RORγt expression of γδ T cells in a STAT5-dependent manner. Collectively, this study suggested that the interplay between IL and 2 and other pro-inflammatory cytokines could trigger the rapid IL-17 production from innate γδ T cells, thus to orchestrate an inflammatory response before the development of adaptive Th17 cells.
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Affiliation(s)
- Tingting Li
- Department of Gastroenterology, The Second Medical Center, Chinese PLA General Hospital, No. 28 Fuxing Road, Beijing 100853, China; National Clinical Research Center for Geriatric Diseases, Chinese PLA General Hospital, No. 28 Fuxing Road, Beijing 100853, China; State Key Laboratory of Kidney Diseases, Chinese PLA General Hospital, No. 28 Fuxing Road, Beijing 100853, China
| | - Yaxin Zhou
- Department of Clinical Immunology, Xijing Hospital, Air Force Medical University (Fourth Military Medical University), No.127 Changle West Road, Xi'an 710032, China
| | - Xi Sun
- Department of Gastroenterology, The Second Medical Center, Chinese PLA General Hospital, No. 28 Fuxing Road, Beijing 100853, China
| | - Yang Bian
- Department of Neurology, The Sixth Medical Center, Chinese PLA General Hospital, No.6 Fucheng Road, Beijing 100048, China
| | - Kunyu Wang
- Department of Neurology, The Sixth Medical Center, Chinese PLA General Hospital, No.6 Fucheng Road, Beijing 100048, China
| | - Qifeng Guo
- Department of Neurology, The Sixth Medical Center, Chinese PLA General Hospital, No.6 Fucheng Road, Beijing 100048, China
| | - Qingqing Wang
- Department of Neurology, The Sixth Medical Center, Chinese PLA General Hospital, No.6 Fucheng Road, Beijing 100048, China
| | - Feng Qiu
- Department of Neurology, The Sixth Medical Center, Chinese PLA General Hospital, No.6 Fucheng Road, Beijing 100048, China.
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Yang MG, Sun L, Han J, Zheng C, Liang H, Zhu J, Jin T. Biological characteristics of transcription factor RelB in different immune cell types: implications for the treatment of multiple sclerosis. Mol Brain 2019; 12:115. [PMID: 31881915 PMCID: PMC6935142 DOI: 10.1186/s13041-019-0532-6] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2019] [Accepted: 12/04/2019] [Indexed: 12/22/2022] Open
Abstract
Transcription factor RelB is a member of the nuclear factror-kappa B (NF-κB) family, which plays a crucial role in mediating immune responses. Plenty of studies have demonstrated that RelB actively contributes to lymphoid organ development, dendritic cells maturation and function and T cells differentiation, as well as B cell development and survival. RelB deficiency may cause a variety of immunological disorders in both mice and humans. Multiple sclerosis (MS) is an inflammatory and demyelinating disease of the central nervous system which involves a board of immune cell populations. Thereby, RelB may exert an impact on MS by modulating the functions of dendritic cells and the differentiation of T cells and B cells. Despite intensive research, the role of RelB in MS and its animal model, experimental autoimmune encephalomyelitis, is still unclear. Herein, we give an overview of the biological characters of RelB, summarize the updated knowledge regarding the role of RelB in different cell types that contribute to MS pathogenesis and discuss the potential RelB-targeted therapeutic implications for MS.
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Affiliation(s)
- Meng-Ge Yang
- Department of Neurology and Neuroscience Center, The First Hospital of Jilin University, Xinmin Street 71#, Changchun, 130021, China
| | - Li Sun
- Department of Neurology and Neuroscience Center, The First Hospital of Jilin University, Xinmin Street 71#, Changchun, 130021, China
| | - Jinming Han
- Department of Neurology and Neuroscience Center, The First Hospital of Jilin University, Xinmin Street 71#, Changchun, 130021, China
- Present address: Department of Clinical Neuroscience, Karolinska Institute, Stockholm, Sweden
| | - Chao Zheng
- Department of Neurology and Neuroscience Center, The First Hospital of Jilin University, Xinmin Street 71#, Changchun, 130021, China
| | - Hudong Liang
- Department of Neurology and Neuroscience Center, The First Hospital of Jilin University, Xinmin Street 71#, Changchun, 130021, China
| | - Jie Zhu
- Department of Neurology and Neuroscience Center, The First Hospital of Jilin University, Xinmin Street 71#, Changchun, 130021, China
- Department of Neurobiology, Care Sciences and Society, Karolinska Institute, Karolinska University Hospital Huddinge, Stockholm, Sweden
| | - Tao Jin
- Department of Neurology and Neuroscience Center, The First Hospital of Jilin University, Xinmin Street 71#, Changchun, 130021, China.
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14
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Maimaitijiang G, Watanabe M, Shinoda K, Isobe N, Nakamura Y, Masaki K, Matsushita T, Yoshikai Y, Kira JI. Long-term use of interferon-β in multiple sclerosis increases Vδ1 -Vδ2 -Vγ9 - γδ T cells that are associated with a better outcome. J Neuroinflammation 2019; 16:179. [PMID: 31519178 PMCID: PMC6743159 DOI: 10.1186/s12974-019-1574-5] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2019] [Accepted: 08/29/2019] [Indexed: 12/27/2022] Open
Abstract
Background We previously reported that Vδ2+Vγ9+ γδ T cells were significantly decreased in multiple sclerosis (MS) patients without disease-modifying therapies (untreated MS) and were negatively correlated with Expanded Disability Status Scale (EDSS) scores, suggesting protective roles of Vδ2+Vγ9+ γδ T cells. Interferon-β (IFN-β) is one of the first-line disease-modifying drugs for MS. However, no previous studies have reported changes in γδ T cell subsets under IFN-β treatment. Therefore, we aimed to clarify the effects of the long-term usage of IFN-β on γδ T cell subsets in MS patients. Methods Comprehensive flow cytometric immunophenotyping was performed in 35 untreated MS and 21 MS patients on IFN-β for more than 2 years (IFN-β-treated MS) including eight super-responders fulfilling no evidence of disease activity criteria, and 44 healthy controls (HCs). Results The percentages of Vδ2+Vγ9+ cells in γδ T cells were significantly lower in untreated and IFN-β-treated MS patients than in HCs. By contrast, the percentages of Vδ1−Vδ2−Vγ9− cells in γδ T cells were markedly higher in IFN-β-treated MS patients than in HCs and untreated MS patients (both p < 0.001). A significant negative correlation between the percentages of Vδ2+Vγ9+ cells in γδ T cells and EDSS scores was confirmed in untreated MS but not evident in IFN-β-treated MS. Moreover, class-switched memory B cells were decreased in IFN-β-treated MS compared with HCs (p < 0.001) and untreated MS patients (p = 0.006). Interestingly, the percentages of Vδ1−Vδ2−Vγ9− cells in γδ T cells were negatively correlated with class-switched memory B cell percentages in all MS patients (r = − 0.369, p = 0.005), and the percentages of Vδ1−Vδ2−Vγ9− cells in Vδ1−Vδ2− γδ T cells were negatively correlated with EDSS scores only in IFN-β super-responders (r = − 0.976, p < 0.001). Conclusions The present study suggests that long-term usage of IFN-β increases Vδ1−Vδ2−Vγ9− γδ T cells, which are associated with a better outcome, especially in IFN-β super-responders. Thus, increased Vδ1−Vδ2−Vγ9− cells together with decreased class-switched memory B cells may contribute to the suppression of disease activity in MS patients under IFN-β treatment. Electronic supplementary material The online version of this article (10.1186/s12974-019-1574-5) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Guzailiayi Maimaitijiang
- Department of Neurology, Neurological Institute, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan
| | - Mitsuru Watanabe
- Department of Neurology, Neurological Institute, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan
| | - Koji Shinoda
- Department of Neurology, Neurological Institute, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan
| | - Noriko Isobe
- Department of Neurological Therapeutics, Neurological Institute, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan
| | - Yuri Nakamura
- Department of Neurology, Neurological Institute, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan
| | - Katsuhisa Masaki
- Department of Neurology, Neurological Institute, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan
| | - Takuya Matsushita
- Department of Neurology, Neurological Institute, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan
| | - Yasunobu Yoshikai
- Division of Host Defense, Medical Institute of Bioregulation, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan
| | - Jun-Ichi Kira
- Department of Neurology, Neurological Institute, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan.
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15
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Saligrama N, Zhao F, Sikora MJ, Serratelli WS, Fernandes RA, Louis DM, Yao W, Ji X, Idoyaga J, Mahajan VB, Steinmetz LM, Chien YH, Hauser SL, Oksenberg JR, Garcia KC, Davis MM. Opposing T cell responses in experimental autoimmune encephalomyelitis. Nature 2019; 572:481-487. [PMID: 31391585 PMCID: PMC7145319 DOI: 10.1038/s41586-019-1467-x] [Citation(s) in RCA: 146] [Impact Index Per Article: 24.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2018] [Accepted: 07/05/2019] [Indexed: 11/30/2022]
Abstract
Experimental autoimmune encephalomyelitis is a model for multiple sclerosis. Here we show that induction generates successive waves of clonally expanded CD4+, CD8+ and γδ+ T cells in the blood and central nervous system, similar to gluten-challenge studies of patients with coeliac disease. We also find major expansions of CD8+ T cells in patients with multiple sclerosis. In autoimmune encephalomyelitis, we find that most expanded CD4+ T cells are specific for the inducing myelin peptide MOG35-55. By contrast, surrogate peptides derived from a yeast peptide major histocompatibility complex library of some of the clonally expanded CD8+ T cells inhibit disease by suppressing the proliferation of MOG-specific CD4+ T cells. These results suggest that the induction of autoreactive CD4+ T cells triggers an opposing mobilization of regulatory CD8+ T cells.
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Affiliation(s)
- Naresha Saligrama
- Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, CA, USA
- Institute of Immunity, Transplantation and Infection, Stanford University School of Medicine, Stanford, CA, USA
| | - Fan Zhao
- Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, CA, USA
| | - Michael J Sikora
- Department of Genetics, Stanford University School of Medicine, Stanford, CA, USA
| | - William S Serratelli
- Institute of Immunity, Transplantation and Infection, Stanford University School of Medicine, Stanford, CA, USA
| | - Ricardo A Fernandes
- Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA, USA
| | - David M Louis
- Institute of Immunity, Transplantation and Infection, Stanford University School of Medicine, Stanford, CA, USA
| | - Winnie Yao
- Institute of Immunity, Transplantation and Infection, Stanford University School of Medicine, Stanford, CA, USA
| | - Xuhuai Ji
- Human Immune Monitoring Center, Stanford University School of Medicine, Stanford, CA, USA
| | - Juliana Idoyaga
- Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, CA, USA
| | - Vinit B Mahajan
- Byers Eye Institute, Department of Ophthalmology, Stanford University, Palo Alto, CA, USA
- Veterans Affairs Palo Alto Health Care, Palo Alto, CA, USA
| | - Lars M Steinmetz
- Department of Genetics, Stanford University School of Medicine, Stanford, CA, USA
- Stanford Genome Technology Center, Stanford University, Palo Alto, CA, USA
- European Molecular Biology Laboratory (EMBL), Genome Biology Unit, Heidelberg, Germany
| | - Yueh-Hsiu Chien
- Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, CA, USA
- Institute of Immunity, Transplantation and Infection, Stanford University School of Medicine, Stanford, CA, USA
- Program in Immunology, Department of Microbiology and Immunology, Stanford University, Stanford, CA, USA
| | - Stephen L Hauser
- Department of Neurology and UCSF Weill Institute for Neurosciences, University of California, San Francisco, CA, USA
| | - Jorge R Oksenberg
- Department of Neurology and UCSF Weill Institute for Neurosciences, University of California, San Francisco, CA, USA
| | - K Christopher Garcia
- Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA, USA
- Department of Structural Biology, Stanford University School of Medicine, Stanford, CA, USA
- The Howard Hughes Medical Institute, Stanford University School of Medicine, Stanford, CA, USA
| | - Mark M Davis
- Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, CA, USA.
- Institute of Immunity, Transplantation and Infection, Stanford University School of Medicine, Stanford, CA, USA.
- The Howard Hughes Medical Institute, Stanford University School of Medicine, Stanford, CA, USA.
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16
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Liaw K, Zhang Z, Kannan S. Neuronanotechnology for brain regeneration. Adv Drug Deliv Rev 2019; 148:3-18. [PMID: 31668648 DOI: 10.1016/j.addr.2019.04.004] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2018] [Revised: 02/16/2019] [Accepted: 04/15/2019] [Indexed: 12/16/2022]
Abstract
Identifying and harnessing regenerative pathways while suppressing the growth-inhibiting processes of the biological response to injury is the central goal of stimulating neurogenesis after central nervous system (CNS) injury. However, due to the complexity of the mature CNS involving a plethora of cellular pathways and extracellular cues, as well as difficulties in accessibility without highly invasive procedures, clinical successes of regenerative medicine for CNS injuries have been extremely limited. Current interventions primarily focus on stabilization and mitigation of further neuronal death rather than direct stimulation of neurogenesis. In the past few decades, nanotechnology has offered substantial innovations to the field of regenerative medicine. Their nanoscale features allow for the fine tuning of biological interactions for enhancing drug delivery and stimulating cellular processes. This review gives an overview of nanotechnology applications in CNS regeneration organized according to cellular and extracellular targets and discuss future directions for the field.
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17
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Cavalcanti De Albuquerque R, Granato A, Silva Castro I, Carvalho Torres R, Santos Souza F, Lima MA, Celestino Bezerra Leite AC, de Melo Espíndola O, Echevarria-Lima J. Phenotypic and functional changes in gamma delta T lymphocytes from HTLV-1 carriers. J Leukoc Biol 2019; 106:607-618. [PMID: 31287591 DOI: 10.1002/jlb.ma1118-467r] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2019] [Revised: 04/11/2019] [Accepted: 06/10/2019] [Indexed: 12/19/2022] Open
Abstract
Human T-cell lymphotropic virus type-1 (HTLV-1) is the etiologic agent of HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP), which is a chronic inflammatory disease that leads to gradual loss of motor movement as a result of the death of spinal cord cells through immune mediated mechanisms. The risk to develop HAM/TSP disease positively correlates with the magnitude of HTLV-1 proviral load. Gamma-delta T lymphocytes have been recognized as important players in a variety of infectious diseases. Therefore, we have investigated interactions between HTLV-1 infection and γδ T lymphocytes during HAM/TSP. Similar frequencies of total γδ T lymphocytes and their Vγ9δ2+ and Vγ9δ2neg subpopulations were observed in HAM/TSP patients. However, T lymphocytes obtained from HTLV-1 carriers displayed significantly higher rates of spontaneous proliferation and NKp30 expression when compared to cells from uninfected donors. In addition, an important decrease in the frequency of granzyme B+ γδ T lymphocytes (approximately 50%) was observed in HAM/TSP patients. Higher proportion of IFN-γ+ γδ T lymphocytes was found in HTLV-1-infected patients, which positively correlated with the HTLV-1 proviral load in peripheral blood mononuclear cells. Collectively, our data indicates that HTLV-1 infection leads to phenotypic and functional changes in the population of γδ T lymphocyte population, suggesting that HTLV-1 infection modulates functions associated to these cells, which might be involved in controlling the infection or in the development of HTLV-1-associated diseases.
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Affiliation(s)
- Raquel Cavalcanti De Albuquerque
- Laboratório de Imunologia Básica e Aplicada, Instituto de Microbiologia Paulo de Góes, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
- Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
| | - Alessandra Granato
- Laboratório de Imunologia Básica e Aplicada, Instituto de Microbiologia Paulo de Góes, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
- Program in Genetics and Genome Biology, Hospital for Sick Children, Toronto, Canada
| | - Isabela Silva Castro
- Laboratório de Imunologia Básica e Aplicada, Instituto de Microbiologia Paulo de Góes, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
| | - Rafael Carvalho Torres
- Plataforma de Imuno-Análise, Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
| | - Flávia Santos Souza
- Laboratório de Pesquisa Clínica em Neuroinfecções, Instituto Nacional de Infectologia Evandro Chagas (INI), Fundação Oswaldo Cruz (Fiocruz), Rio de Janeiro, Brazil
| | - Marco Antonio Lima
- Laboratório de Pesquisa Clínica em Neuroinfecções, Instituto Nacional de Infectologia Evandro Chagas (INI), Fundação Oswaldo Cruz (Fiocruz), Rio de Janeiro, Brazil
| | - Ana Claudia Celestino Bezerra Leite
- Laboratório de Pesquisa Clínica em Neuroinfecções, Instituto Nacional de Infectologia Evandro Chagas (INI), Fundação Oswaldo Cruz (Fiocruz), Rio de Janeiro, Brazil
| | - Otávio de Melo Espíndola
- Laboratório de Pesquisa Clínica em Neuroinfecções, Instituto Nacional de Infectologia Evandro Chagas (INI), Fundação Oswaldo Cruz (Fiocruz), Rio de Janeiro, Brazil
| | - Juliana Echevarria-Lima
- Laboratório de Imunologia Básica e Aplicada, Instituto de Microbiologia Paulo de Góes, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
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18
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Muir FGW, Samadi-Bahrami Z, Moore GRW, Quandt JA. Expression of CD1d by astrocytes corresponds with relative activity in multiple sclerosis lesions. Brain Pathol 2019; 30:26-35. [PMID: 31050367 PMCID: PMC6916356 DOI: 10.1111/bpa.12733] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2018] [Accepted: 04/23/2019] [Indexed: 12/23/2022] Open
Abstract
The CD1 protein family present lipid antigens to the immune system. CD1d has been observed in the CNS of MS patients, yet no studies have quantitatively characterized this expression and related it to inflammatory demyelinative activity in MS plaques. In this study, we set out to localize and quantify the presence of CD1d expression by astrocytes in MS brain tissue lesions. Formalin‐fixed, paraffin‐embedded MS and control brain tissues were examined. Lesions were classified as active, chronic active or chronic silent. Using immunofluorescence, the density of CD1d‐positive cells was determined in active lesions, chronic active lesion edges and chronic active lesion centers. The percentage of CD1d‐positive cells that were GFAP‐positive was also determined in each of these regions. CD1d immunoreactivity was significantly increased in MS compared to control tissue, was significantly more prevalent in areas of active demyelination, and colocalized with GFAP‐positive reactive astrocytes. Increases of CD1d immunoreactivity in the CNS of MS patients being greatest in areas of active demyelination and localized to GFAP‐positive astrocytes lend support to the hypothesis of a lipid‐targeted autoimmune process contributing to the pathogenesis of MS.
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Affiliation(s)
- Fraser G W Muir
- Department of Pathology & Laboratory Medicine, International Collaboration on Repair Discoveries (ICORD), University of British Columbia, Vancouver, Canada
| | - Zahra Samadi-Bahrami
- Department of Pathology & Laboratory Medicine, International Collaboration on Repair Discoveries (ICORD), University of British Columbia, Vancouver, Canada
| | - George R Wayne Moore
- Department of Pathology & Laboratory Medicine, Department of Medicine (Neurology), International Collaboration on Repair Discoveries (ICORD), University of British Columbia, Vancouver, Canada
| | - Jacqueline A Quandt
- Department of Pathology & Laboratory Medicine, University of British Columbia, Vancouver, Canada
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19
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Van Kaer L, Postoak JL, Wang C, Yang G, Wu L. Innate, innate-like and adaptive lymphocytes in the pathogenesis of MS and EAE. Cell Mol Immunol 2019; 16:531-539. [PMID: 30874627 PMCID: PMC6804597 DOI: 10.1038/s41423-019-0221-5] [Citation(s) in RCA: 101] [Impact Index Per Article: 16.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2019] [Accepted: 02/22/2019] [Indexed: 12/11/2022] Open
Abstract
Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system (CNS) in which the immune system damages the protective insulation surrounding the nerve fibers that project from neurons. A hallmark of MS and its animal model, experimental autoimmune encephalomyelitis (EAE), is autoimmunity against proteins of the myelin sheath. Most studies in this field have focused on the roles of CD4+ T lymphocytes, which form part of the adaptive immune system as both mediators and regulators in disease pathogenesis. Consequently, the treatments for MS often target the inflammatory CD4+ T-cell responses. However, many other lymphocyte subsets contribute to the pathophysiology of MS and EAE, and these subsets include CD8+ T cells and B cells of the adaptive immune system, lymphocytes of the innate immune system such as natural killer cells, and subsets of innate-like T and B lymphocytes such as γδ T cells, natural killer T cells, and mucosal-associated invariant T cells. Several of these lymphocyte subsets can act as mediators of CNS inflammation, whereas others exhibit immunoregulatory functions in disease. Importantly, the efficacy of some MS treatments might be mediated in part by effects on lymphocytes other than CD4+ T cells. Here we review the contributions of distinct subsets of lymphocytes on the pathogenesis of MS and EAE, with an emphasis on lymphocytes other than CD4+ T cells. A better understanding of the distinct lymphocyte subsets that contribute to the pathophysiology of MS and its experimental models will inform the development of novel therapeutic approaches.
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Affiliation(s)
- Luc Van Kaer
- Department of Pathology, Microbiology and Immunology, Vanderbilt University School of Medicine, Nashville, TN, 37232, USA.
| | - Joshua L Postoak
- Department of Pathology, Microbiology and Immunology, Vanderbilt University School of Medicine, Nashville, TN, 37232, USA
| | - Chuan Wang
- Department of Pathology, Microbiology and Immunology, Vanderbilt University School of Medicine, Nashville, TN, 37232, USA
| | - Guan Yang
- Department of Pathology, Microbiology and Immunology, Vanderbilt University School of Medicine, Nashville, TN, 37232, USA
| | - Lan Wu
- Department of Pathology, Microbiology and Immunology, Vanderbilt University School of Medicine, Nashville, TN, 37232, USA
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20
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Zarobkiewicz MK, Kowalska W, Roliński J, Bojarska-Junak AA. γδ T lymphocytes in the pathogenesis of multiple sclerosis and experimental autoimmune encephalomyelitis. J Neuroimmunol 2019; 330:67-73. [PMID: 30831520 DOI: 10.1016/j.jneuroim.2019.02.009] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2018] [Revised: 02/07/2019] [Accepted: 02/17/2019] [Indexed: 12/18/2022]
Abstract
The aim of the current review is to summarize the results of studies on the role of γδ T cells in the pathogenesis of multiple sclerosis and its animal model - the experimental autoimmune encephalomyelitis. Despite the fact that numerous studies have been performed, the role of γδ T is still not fully understood. It seems that there are two distinct subpopulations - one exacerbating the disease (IL-17-producing) and the other playing a protective role (IFN-γ-secreting). Nevertheless, future studies are required for an understanding of γδ T cells role in multiple sclerosis.
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Affiliation(s)
| | - Wioleta Kowalska
- Chair and Department of Clinical Immunology, Medical University of Lublin, Poland
| | - Jacek Roliński
- Chair and Department of Clinical Immunology, Medical University of Lublin, Poland
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21
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Maimaitijiang G, Shinoda K, Nakamura Y, Masaki K, Matsushita T, Isobe N, Yamasaki R, Yoshikai Y, Kira JI. Association of Decreased Percentage of Vδ2 +Vγ9 + γδ T Cells With Disease Severity in Multiple Sclerosis. Front Immunol 2018; 9:748. [PMID: 29692781 PMCID: PMC5903009 DOI: 10.3389/fimmu.2018.00748] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2017] [Accepted: 03/26/2018] [Indexed: 12/31/2022] Open
Abstract
We recently reported that deletion-type copy number variations of the T cell receptor (TCR) γ, α, and δ genes greatly enhanced susceptibility to multiple sclerosis (MS). However, the effect of abnormal TCR γδ gene rearrangement on MS pathogenesis remains unknown. In the present study, we aimed to clarify γδ TCR repertoire alterations and their relationship to clinical and immunological parameters in MS patients by comprehensive flow cytometric immunophenotyping. Peripheral blood mononuclear cells obtained from 30 untreated MS patients in remission and 23 age- and sex-matched healthy controls (HCs) were stained for surface markers and intracellular cytokines after stimulation with phorbol 12-myristate 13-acetate and ionomycin, and analyzed by flow cytometry. MS patients showed significantly decreased percentages of Vδ2+ and Vδ2+Vγ9+ cells in γδ T cells (pcorr = 0.0297 and pcorr = 0.0288, respectively) and elevated Vδ1/Vδ2 ratios compared with HCs (p = 0.0033). The percentages of interferon (IFN)-γ+Vδ2+ and interleukin (IL)-17A+IFN-γ+Vδ2+ cells in γδ T cells, as well as IFN-γ+ cells in Vδ2+ γδ T cells, were significantly lower in MS patients than in HCs (pcorr < 0.0009, pcorr = 0.0135, and pcorr = 0.0054, respectively). The percentages of Vδ2+ and Vδ2+Vγ9+ cells in γδ T cells were negatively correlated with both the Expanded Disability Status Scale score (r = -0.5006, p = 0.0048; and r = -0.5040, p = 0.0045, respectively) and Multiple Sclerosis Severity Score (r = -0.4682, p = 0.0091; and r = -0.4706, p = 0.0087, respectively), but not with age at disease onset, disease duration, or annualized relapse rate. In HCs, the percentages of Vδ2+ and Vδ2+Vγ9+ cells of total CD3+ T cells had strong positive correlations with the percentage of CD25+CD127low/- cells in CD4+ T cells (r = 0.7826, p < 0.0001; and r = 0.7848, p < 0.0001, respectively), whereas such correlations were totally absent in MS patients. These findings suggest that decreased Vδ2+Vγ9+ γδ T cells are associated with disability in MS. Therefore, the Vδ1/Vδ2 ratio might be a candidate biomarker for predicting disease severity in MS.
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Affiliation(s)
- Guzailiayi Maimaitijiang
- Department of Neurology, Neurological Institute, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Koji Shinoda
- Department of Neurology, Neurological Institute, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Yuri Nakamura
- Department of Neurology, Neurological Institute, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Katsuhisa Masaki
- Department of Neurology, Neurological Institute, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Takuya Matsushita
- Department of Neurology, Neurological Institute, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Noriko Isobe
- Department of Neurology, Neurological Institute, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Ryo Yamasaki
- Department of Neurology, Neurological Institute, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Yasunobu Yoshikai
- Division of Host Defense, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan
| | - Jun-Ichi Kira
- Department of Neurology, Neurological Institute, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
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Taheri M, Sayad A. Investigating the exon 6 sequence changes of interleukin 7 receptor A (IL7RA) gene in patients with relapsing-remitting multiple sclerosis. Hum Antibodies 2018; 26:43-48. [PMID: 28582853 DOI: 10.3233/hab-170320] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/07/2023]
Abstract
BACKGROUND Interleukin 7 receptor alpha (IL7RA) gene that encodes a subunit of IL7 receptor has been reported to be associated with different immunologic disease. OBJECTIVE Multiple Sclerosis (MS) patients have shown an aberrant blood level of soluble form of IL7R protein. The genomic changes in the sequence of this gene have been suggested to be correlated with its altered splicing specially, variants in the exon 6 of the gene have been reported to influence the maintenance or skipping of this exon and control the soluble or insoluble form of the final product. In order to evaluate this changes in the IL7RA gene and to determine a possible correlation between these changes and the MS susceptibility the whole sequence of the exon 6 and 7 and their flanking sequences were analyzed. METHODS In this regard, we investigate the sequence changes of the exon 6 and 7 of the IL7RA gene in 75 relapsing-remitting MS patients and compare the results with 75 healthy control using sequence analyzing. RESULTS The results of the sequence analysis were used in two aspects. The allelic and genotypic estimated frequencies of a reported risk variant rs6897932 in patients and controls in our population confirmed its association with the disease (P= 0.009, OR = 6.273, for TT genotype). Also, we report a possible hazardous cutoff for changes in a potential exon splicing silencer element (ESS (nt. 20-24)) and its correlation with rs6897932 to confer the risk of developing MS. CONCLUSION In conclusion our results confirm the association between IL7RA exon 6 sequence changes and increased susceptibility for multiple sclerosis.
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Affiliation(s)
- Mohammad Taheri
- Department of Medical Genetics, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
- Urogenital Stem Cell Research Center, Shahid Labbafi Nejad Educational Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Arezou Sayad
- Department of Medical Genetics, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
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Vermijlen D, Gatti D, Kouzeli A, Rus T, Eberl M. γδ T cell responses: How many ligands will it take till we know? Semin Cell Dev Biol 2018; 84:75-86. [PMID: 29402644 DOI: 10.1016/j.semcdb.2017.10.009] [Citation(s) in RCA: 79] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2017] [Revised: 09/06/2017] [Accepted: 10/09/2017] [Indexed: 12/20/2022]
Abstract
γδ T cells constitute a sizeable and non-redundant fraction of the total T cell pool in all jawed vertebrates, but in contrast to conventional αβ T cells they are not restricted by classical MHC molecules. Progress in our understanding of the role of γδ T cells in the immune system has been hampered, and is being hampered, by the considerable lack of knowledge regarding the antigens γδ T cells respond to. The past few years have seen a wealth of data regarding the TCR repertoires of distinct γδ T cell populations and a growing list of confirmed and proposed molecules that are recognised by γδ T cells in different species. Yet, the physiological contexts underlying the often restricted TCR usage and the chemical diversity of γδ T cell ligands remain largely unclear, and only few structural studies have confirmed direct ligand recognition by the TCR. We here review the latest progress in the identification and validation of putative γδ T cell ligands and discuss the implications of such findings for γδ T cell responses in health and disease.
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Affiliation(s)
- David Vermijlen
- Department of Pharmacotherapy and Pharmaceutics and Institute for Medical Immunology, Université Libre de Bruxelles (ULB), Belgium.
| | - Deborah Gatti
- Department of Pharmacotherapy and Pharmaceutics and Institute for Medical Immunology, Université Libre de Bruxelles (ULB), Belgium
| | - Ariadni Kouzeli
- Division of Infection and Immunity, School of Medicine, Cardiff University, Cardiff, United Kingdom
| | - Teja Rus
- Division of Infection and Immunity, School of Medicine, Cardiff University, Cardiff, United Kingdom
| | - Matthias Eberl
- Division of Infection and Immunity, School of Medicine, Cardiff University, Cardiff, United Kingdom; Systems Immunity Research Institute, Cardiff University, Cardiff, United Kingdom.
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24
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Innately versatile: γδ17 T cells in inflammatory and autoimmune diseases. J Autoimmun 2018; 87:26-37. [DOI: 10.1016/j.jaut.2017.11.006] [Citation(s) in RCA: 72] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2017] [Accepted: 11/20/2017] [Indexed: 02/06/2023]
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McGinley AM, Edwards SC, Raverdeau M, Mills KHG. Th17 cells, γδ T cells and their interplay in EAE and multiple sclerosis. J Autoimmun 2018; 87:S0896-8411(18)30007-6. [PMID: 29395738 DOI: 10.1016/j.jaut.2018.01.001] [Citation(s) in RCA: 86] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2018] [Accepted: 01/04/2018] [Indexed: 01/09/2023]
Abstract
Experimental autoimmune encephalomyelitis (EAE) is an animal model of multiple sclerosis (MS) that shares many features with the human disease. This review will focus on the role of IL-17-secreting CD4 and γδ T cells in EAE and MS, the plasticity of Th17 cells in vivo and the application of these findings to the understating of the pathogenesis and the development of new treatments for MS. There is convincing evidence that IL-17-secreting CD4 T cells (Th17 cells) and IL-17-secreting γδ T cells play a critical pathogenic role in central nervous system (CNS) inflammation in EAE and MS. Indeed a significant number of the major discoveries on the pathogenic role of IL-17-secreting T cells in autoimmunity were made in the EAE model. These included the first demonstration that IL-23-activated IL-17-secreting T cells are the key T cells in driving autoimmune disease pathology. Although the early studies on IL-17 focused on Th17 cells, it was later demonstrated that γδ T cells were an important early source of IL-17 and IL-21 that helped amplify IL-17 production by Th17 cells in autoimmune diseases. Furthermore, it emerged that Th1 cells can also have encephalitogenic activity and that there was considerable plasticity in these T cell responses, with Th17 cells reverting to a Th1 phenotype in vivo. This questioned the pathogenic role of IL-17 and suggested that other cytokines, such as IFN-γ, GM-CSF and TNF, may be important. Nevertheless, biological drugs that target the IL-23-IL-17 pathway are highly effective in treating human psoriasis and are showing promise in the treatment of relapsing remitting MS and other T-cell mediated autoimmune diseases.
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Affiliation(s)
- Aoife M McGinley
- School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin 2, Ireland
| | - Sarah C Edwards
- School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin 2, Ireland
| | - Mathilde Raverdeau
- School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin 2, Ireland
| | - Kingston H G Mills
- School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin 2, Ireland.
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26
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Hiltensperger M, Korn T. The Interleukin (IL)-23/T helper (Th)17 Axis in Experimental Autoimmune Encephalomyelitis and Multiple Sclerosis. Cold Spring Harb Perspect Med 2018; 8:cshperspect.a029637. [PMID: 29101111 DOI: 10.1101/cshperspect.a029637] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
T helper (Th)17 cells are responsible for host defense against fungi and certain extracellular bacteria but have also been reported to play a role in a variety of autoimmune diseases. Th17 cells respond to environmental cues, are very plastic, and might also be involved in tissue homeostasis and regeneration. The imprinting of pathogenic properties in Th17 cells in autoimmunity seems highly dependent on interleukin (IL)-23. Since Th17 cells were first described in experimental autoimmune encephalomyelitis, they have been suggested to also promote tissue damage in multiple sclerosis (MS). Indeed, some studies linked Th17 cells to disease severity in MS, and the efficacy of anti-IL-17A therapy in MS supported this idea. In this review, we will summarize molecular features of Th17 cells and discuss the evidence for their function in experimental models of autoimmune diseases and MS.
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Affiliation(s)
- Michael Hiltensperger
- Klinikum rechts der Isar, Department of Neurology, Technische Universität München, 81675 Munich, Germany
| | - Thomas Korn
- Klinikum rechts der Isar, Department of Neurology, Technische Universität München, 81675 Munich, Germany.,Munich Cluster for Systems Neurology (SyNergy), 81377 Munich, Germany
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27
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The influence and impact of ageing and immunosenescence (ISC) on adaptive immunity during multiple sclerosis (MS) and the animal counterpart experimental autoimmune encephalomyelitis (EAE). Ageing Res Rev 2018; 41:64-81. [PMID: 29101043 DOI: 10.1016/j.arr.2017.10.005] [Citation(s) in RCA: 36] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2017] [Revised: 10/23/2017] [Accepted: 10/25/2017] [Indexed: 12/21/2022]
Abstract
The human ageing process encompasses mechanisms that effect a decline in homeostasis with increased susceptibility to disease and the development of chronic life-threatening illness. Increasing age affects the immune system which undergoes a progressive loss of efficiency, termed immunosenescence (ISC), to impact on quantitative and functional aspects of innate and adaptive immunity. The human demyelinating disease multiple sclerosis (MS) and the corresponding animal model experimental autoimmune encephalomyelitis (EAE) are strongly governed by immunological events that primarily involve the adaptive arm of the immune response. MS and EAE are frequently characterised by a chronic pathology and a protracted disease course which thereby creates the potential for exposure to the inherent, on-going effects and consequences of ISC. Collective evidence is presented to confirm the occurrence of established and unendorsed biological markers of ISC during the development of both diseases. Moreover, results are discussed from studies during the course of MS and EAE that reveal a premature upregulation of ISC-related biomarkers which indicates untimely alterations to the adaptive immune system. The effects of ISC and a prematurely aged immune system on autoimmune-associated neurodegenerative conditions such as MS and EAE are largely unknown but current evaluation of data justifies and encourages further investigation.
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28
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T Lymphocytes and Autoimmunity. INTERNATIONAL REVIEW OF CELL AND MOLECULAR BIOLOGY 2018; 341:125-168. [DOI: 10.1016/bs.ircmb.2018.05.008] [Citation(s) in RCA: 48] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
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Albertsson AM, Zhang X, Vontell R, Bi D, Bronson RT, Supramaniam V, Baburamani AA, Hua S, Nazmi A, Cardell S, Zhu C, Cantor H, Mallard C, Hagberg H, Leavenworth JW, Wang X. γδ T Cells Contribute to Injury in the Developing Brain. THE AMERICAN JOURNAL OF PATHOLOGY 2017; 188:757-767. [PMID: 29248460 PMCID: PMC5840494 DOI: 10.1016/j.ajpath.2017.11.012] [Citation(s) in RCA: 42] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 08/24/2017] [Revised: 10/11/2017] [Accepted: 11/07/2017] [Indexed: 01/04/2023]
Abstract
Brain injury in premature infants, especially periventricular leukomalacia, is an important cause of neurologic disabilities. Inflammation contributes to perinatal brain injury development, but the essential mediators that lead to early-life brain injury remain largely unknown. Neonates have reduced capacity for mounting conventional αβT-cell responses. However, γδT cells are already functionally competent during early development and are important in early-life immunity. We investigated the potential contribution of γδT cells to preterm brain injury using postmortem brains from human preterm infants with periventricular leukomalacia and two animal models of preterm brain injury—the hypoxic-ischemic mouse model and a fetal sheep asphyxia model. Large numbers of γδT cells were observed in the brains of mice, sheep, and postmortem preterm infants after injury, and depletion of γδT cells provided protection in the mouse model. The common γδT-cell–associated cytokines interferon-γ and IL-17A were not detectable in the brain. Although there were increased mRNA levels of Il17f and Il22 in the mouse brains after injury, neither IL-17F nor IL-22 cytokines contributed to preterm brain injury. These findings highlight unique features of injury in the developing brain, where, unlike injury in the mature brain, γδT cells function as initiators of injury independently of common γδT-cell–associated cytokines. This finding will help to identify therapeutic targets for preventing or treating preterm infants with brain injury.
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Affiliation(s)
- Anna-Maj Albertsson
- Perinatal Center, Department of Physiology, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Xiaoli Zhang
- Perinatal Center, Department of Physiology, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden; Department of Pediatrics, The Third Affiliated Hospital of Zhengzhou University, Zhengzhou, China; Henan Provincial Key Laboratory of Child Brain Injury, Zhengzhou, China
| | - Regina Vontell
- Centre for the Developing Brain, Department of Perinatal Imaging and Health, King's College London, St. Thomas' Hospital, London, United Kingdom
| | - Dan Bi
- Perinatal Center, Department of Physiology, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden; Department of Pediatrics, The Third Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Roderick T Bronson
- Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts; Department of Microbiology and Immunobiology, Division of Immunology, Harvard Medical School, Boston, Massachusetts
| | - Veena Supramaniam
- Centre for the Developing Brain, Department of Perinatal Imaging and Health, King's College London, St. Thomas' Hospital, London, United Kingdom
| | - Ana A Baburamani
- Centre for the Developing Brain, Department of Perinatal Imaging and Health, King's College London, St. Thomas' Hospital, London, United Kingdom
| | - Sha Hua
- Perinatal Center, Department of Physiology, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden; Department of Cardiovascular Medicine, Luwan Branch of Shanghai Jiaotong University Medical School Ruijin Hospital, Shanghai, China
| | - Arshed Nazmi
- Perinatal Center, Department of Physiology, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Susanna Cardell
- Department of Microbiology and Immunology, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Changlian Zhu
- Department of Pediatrics, The Third Affiliated Hospital of Zhengzhou University, Zhengzhou, China; Henan Provincial Key Laboratory of Child Brain Injury, Zhengzhou, China; Department of Clinical Neuroscience, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Harvey Cantor
- Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts; Department of Microbiology and Immunobiology, Division of Immunology, Harvard Medical School, Boston, Massachusetts
| | - Carina Mallard
- Perinatal Center, Department of Physiology, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Henrik Hagberg
- Perinatal Center, Department of Physiology, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden; Centre for the Developing Brain, Department of Perinatal Imaging and Health, King's College London, St. Thomas' Hospital, London, United Kingdom; Department of Clinical Sciences, East Hospital, Gothenburg, Sweden
| | - Jianmei W Leavenworth
- Department of Neurosurgery, University of Alabama at Birmingham, Birmingham, Alabama; Department of Microbiology, University of Alabama at Birmingham, Birmingham, Alabama.
| | - Xiaoyang Wang
- Perinatal Center, Department of Physiology, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden; Department of Pediatrics, The Third Affiliated Hospital of Zhengzhou University, Zhengzhou, China.
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30
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Al Nimer F, Jelcic I, Kempf C, Pieper T, Budka H, Sospedra M, Martin R. Phenotypic and functional complexity of brain-infiltrating T cells in Rasmussen encephalitis. NEUROLOGY-NEUROIMMUNOLOGY & NEUROINFLAMMATION 2017; 5:e419. [PMID: 29259996 PMCID: PMC5733246 DOI: 10.1212/nxi.0000000000000419] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/26/2017] [Accepted: 10/04/2017] [Indexed: 11/15/2022]
Abstract
Objective: To characterize the brain-infiltrating immune cell repertoire in Rasmussen encephalitis (RE) with special focus on the subsets, clonality, and their cytokine profile. Methods: The immune cell infiltrate of freshly isolated brain tissue from RE was phenotypically and functionally characterized using immunohistology, flow cytometry, and T-cell receptor (TCR) deep sequencing. Identification of clonally expanded T-cell clones (TCCs) was achieved by combining flow cytometry sorting of CD4+ and CD8+ T cells and high-throughput TCR Vβ-chain sequencing. The most abundant brain-infiltrating TCCs were isolated and functionally characterized. Results: We found that CD4+, CD8+, and also γδ T cells infiltrate the brain tissue in RE. Further analysis surprisingly revealed that not only brain-infiltrating CD8+ but also CD4+ T cells are clonally expanded in RE. All 3 subsets exhibited a Tc1/Th1 phenotype characterized by the production of interferon (IFN)-γ and TNF. Broad cytokine profiling at the clonal level showed strong production of IFN-γ and TNF and also secretion of interleukin (IL)-5, IL-13, and granzyme B, both in CD4+ and CD8+ T cells. Conclusions: CD8+ T cells were until now considered the central players in the immunopathogenesis of RE. Our study adds to previous findings and highlights that CD4+ TCCs and γδ T cells that secrete IFN-γ and TNF are also involved. These findings underline the complexity of T-cell immunity in RE and suggest a specific role for CD4+ T cells in orchestrating the CD8+ T-cell effector immune response.
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Affiliation(s)
- Faiez Al Nimer
- Neuroimmunology and Multiple Sclerosis Research Section (F.A.N., I.J., C.K., M.S., R.M.), Department of Neurology, University Hospital Zurich, Switzerland; Neuropediatric Clinic and Clinic for Neurorehabilitation (T.P.), Epilepsy Center for Children and Adolescents, Schoen Klinik Vogtareuth, Germany; and Institute of Neuropathology (H.B.), University Hospital Zurich, Switzerland
| | - Ivan Jelcic
- Neuroimmunology and Multiple Sclerosis Research Section (F.A.N., I.J., C.K., M.S., R.M.), Department of Neurology, University Hospital Zurich, Switzerland; Neuropediatric Clinic and Clinic for Neurorehabilitation (T.P.), Epilepsy Center for Children and Adolescents, Schoen Klinik Vogtareuth, Germany; and Institute of Neuropathology (H.B.), University Hospital Zurich, Switzerland
| | - Christian Kempf
- Neuroimmunology and Multiple Sclerosis Research Section (F.A.N., I.J., C.K., M.S., R.M.), Department of Neurology, University Hospital Zurich, Switzerland; Neuropediatric Clinic and Clinic for Neurorehabilitation (T.P.), Epilepsy Center for Children and Adolescents, Schoen Klinik Vogtareuth, Germany; and Institute of Neuropathology (H.B.), University Hospital Zurich, Switzerland
| | - Tom Pieper
- Neuroimmunology and Multiple Sclerosis Research Section (F.A.N., I.J., C.K., M.S., R.M.), Department of Neurology, University Hospital Zurich, Switzerland; Neuropediatric Clinic and Clinic for Neurorehabilitation (T.P.), Epilepsy Center for Children and Adolescents, Schoen Klinik Vogtareuth, Germany; and Institute of Neuropathology (H.B.), University Hospital Zurich, Switzerland
| | - Herbert Budka
- Neuroimmunology and Multiple Sclerosis Research Section (F.A.N., I.J., C.K., M.S., R.M.), Department of Neurology, University Hospital Zurich, Switzerland; Neuropediatric Clinic and Clinic for Neurorehabilitation (T.P.), Epilepsy Center for Children and Adolescents, Schoen Klinik Vogtareuth, Germany; and Institute of Neuropathology (H.B.), University Hospital Zurich, Switzerland
| | - Mireia Sospedra
- Neuroimmunology and Multiple Sclerosis Research Section (F.A.N., I.J., C.K., M.S., R.M.), Department of Neurology, University Hospital Zurich, Switzerland; Neuropediatric Clinic and Clinic for Neurorehabilitation (T.P.), Epilepsy Center for Children and Adolescents, Schoen Klinik Vogtareuth, Germany; and Institute of Neuropathology (H.B.), University Hospital Zurich, Switzerland
| | - Roland Martin
- Neuroimmunology and Multiple Sclerosis Research Section (F.A.N., I.J., C.K., M.S., R.M.), Department of Neurology, University Hospital Zurich, Switzerland; Neuropediatric Clinic and Clinic for Neurorehabilitation (T.P.), Epilepsy Center for Children and Adolescents, Schoen Klinik Vogtareuth, Germany; and Institute of Neuropathology (H.B.), University Hospital Zurich, Switzerland
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Pharmacological inhibition of RORγt suppresses the Th17 pathway and alleviates arthritis in vivo. PLoS One 2017; 12:e0188391. [PMID: 29155882 PMCID: PMC5695821 DOI: 10.1371/journal.pone.0188391] [Citation(s) in RCA: 52] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2017] [Accepted: 10/20/2017] [Indexed: 12/12/2022] Open
Abstract
Retinoic acid receptor-related-orphan-receptor-C (RORγt) is the key transcription factor that is driving the differentiation of IL-17 producing T-helper 17 (Th17) cells that are implicated in the pathology of various autoimmune and inflammatory diseases. Based on the importance of RORγt in promoting Th17-driven pathology, there is considerable interest to develop low-molecular-weight compounds with the aim of inhibiting the transcriptional activity of this nuclear hormone receptor. In this article, we describe the in vitro and in vivo pharmacology of a potent and selective small-molecular-weight RORγt inverse agonist. The compound binds to the ligand binding domain (LBD) of RORγt leading to displacement of a co-activator peptide. We show for the first time that a RORγt inverse agonist down-regulates permissive histone H3 acetylation and methylation at the IL17A and IL23R promoter regions, thereby providing insight into the transcriptional inhibition of RORγt-dependent genes. Consistent with this, the compound effectively reduced IL-17A production by polarized human T-cells and γδT-cells and attenuated transcription of RORγt target genes. The inhibitor showed good in vivo efficacy in an antigen-induced arthritis model in rats and reduced the frequencies of IL-17A producing cells in ex vivo recall assays. In summary, we demonstrate that inhibiting RORγt by a low-molecular-weight inhibitor results in efficient and selective blockade of the pro-inflammatory Th17/IL-17A pathway making it an attractive target for Th17-mediated disorders.
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Das D, Anand V, Khandpur S, Sharma VK, Sharma A. T helper type 1 polarizing γδ T cells and Scavenger receptors contribute to the pathogenesis of Pemphigus vulgaris. Immunology 2017; 153:97-104. [PMID: 28815581 DOI: 10.1111/imm.12814] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2017] [Revised: 07/31/2017] [Accepted: 08/08/2017] [Indexed: 01/03/2023] Open
Abstract
γδ T cells and Scavenger receptors are key parts of the innate immune machinery, playing significant roles in regulating immune homeostasis at the epithelial surface. The roles of these immune components are not yet characterized for the autoimmune skin disorder Pemphigus vulgaris (PV). Phenotyping and frequency of γδ T cells estimated by flow cytometry have shown increased frequency of γδ T cells (6·7% versus 4·4%) producing interferon- γ (IFN-γ; 35·2% versus 26·68%) in the circulation of patients compared with controls. Dual cytokine-secreting (IFN-γ and interleukin-4) γδ T cells indicate the plasticity of these cells. The γδ T cells of patients with PV have shown higher cytotoxic potential and the higher frequency of γδ T cells producing IFN-γ shows T helper type 1 polarization. The increased expression of Scavenger receptors expression (CD36 and CD163) could be contributing to the elevated inflammatory environment and immune imbalance in this disease. Targeting the inflammatory γδ T cells and Scavenger receptors may pave the way for novel therapeutics.
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Affiliation(s)
- Dayasagar Das
- Department of Biochemistry, All India Institute of Medical Sciences, New Delhi, India
| | - Vivek Anand
- Department of Biochemistry, All India Institute of Medical Sciences, New Delhi, India
| | - Sujay Khandpur
- Department of Dermatology, All India Institute of Medical Sciences, New Delhi, India
| | - Vinod K Sharma
- Department of Dermatology, All India Institute of Medical Sciences, New Delhi, India
| | - Alpana Sharma
- Department of Biochemistry, All India Institute of Medical Sciences, New Delhi, India
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Impact of aging immune system on neurodegeneration and potential immunotherapies. Prog Neurobiol 2017; 157:2-28. [PMID: 28782588 DOI: 10.1016/j.pneurobio.2017.07.006] [Citation(s) in RCA: 36] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2015] [Revised: 07/25/2017] [Accepted: 07/28/2017] [Indexed: 12/19/2022]
Abstract
The interaction between the nervous and immune systems during aging is an area of avid interest, but many aspects remain unclear. This is due, not only to the complexity of the aging process, but also to a mutual dependency and reciprocal causation of alterations and diseases between both the nervous and immune systems. Aging of the brain drives whole body systemic aging, including aging-related changes of the immune system. In turn, the immune system aging, particularly immunosenescence and T cell aging initiated by thymic involution that are sources of chronic inflammation in the elderly (termed inflammaging), potentially induces brain aging and memory loss in a reciprocal manner. Therefore, immunotherapeutics including modulation of inflammation, vaccination, cellular immune therapies and "protective autoimmunity" provide promising approaches to rejuvenate neuroinflammatory disorders and repair brain injury. In this review, we summarize recent discoveries linking the aging immune system with the development of neurodegeneration. Additionally, we discuss potential rejuvenation strategies, focusing aimed at targeting the aging immune system in an effort to prevent acute brain injury and chronic neurodegeneration during aging.
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Papotto PH, Ribot JC, Silva-Santos B. IL-17+ γδ T cells as kick-starters of inflammation. Nat Immunol 2017; 18:604-611. [DOI: 10.1038/ni.3726] [Citation(s) in RCA: 167] [Impact Index Per Article: 20.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2016] [Accepted: 03/14/2017] [Indexed: 12/12/2022]
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35
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Singh AK, Novakova L, Axelsson M, Malmeström C, Zetterberg H, Lycke J, Cardell SL. High Interferon-γ Uniquely in Vδ1 T Cells Correlates with Markers of Inflammation and Axonal Damage in Early Multiple Sclerosis. Front Immunol 2017; 8:260. [PMID: 28337205 PMCID: PMC5343019 DOI: 10.3389/fimmu.2017.00260] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2016] [Accepted: 02/21/2017] [Indexed: 11/25/2022] Open
Abstract
We have identified a population of T lymphocytes in peripheral blood, Vδ1 TCRγδ T lymphocytes, which unexpectedly was uniquely expressing high production of interferon-γ in newly diagnosed, untreated multiple sclerosis (MS) patients. IFN-γ production in this population distinctly correlated to parameters of clinical disease activity, inflammation, and neuronal damage. These Vδ1 T lymphocytes belong to a population of innate T lymphocytes that recognize antigen in the context of CD1d/CD1c and which include reactivity to the myelin glycosphingolipid sulfatide. Importantly, patients treated with natalizumab, blocking leukocyte transmigration to central nervous system, had completely normalized levels of interferon-γ-producing Vδ1 T lymphocytes. A biomarker and early sign of demyelinating disease in MS is much warranted and would help identify immunopathogenesis and prognosis of disease as well as monitor success with adequate treatment. The present study identifies the Vδ1 T lymphocytes as an early marker of MS and a possible link to understanding the disease etiology.
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Affiliation(s)
- Avadhesh Kumar Singh
- Department of Microbiology and Immunology, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg , Gothenburg , Sweden
| | - Lenka Novakova
- Department of Clinical Neuroscience, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg , Gothenburg , Sweden
| | - Markus Axelsson
- Department of Clinical Neuroscience, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg , Gothenburg , Sweden
| | - Clas Malmeström
- Department of Clinical Neuroscience, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg , Gothenburg , Sweden
| | - Henrik Zetterberg
- Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Mölndal, Sweden; Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden; Department of Molecular Neuroscience, UCL Institute of Neurology, London, UK
| | - Jan Lycke
- Department of Clinical Neuroscience, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg , Gothenburg , Sweden
| | - Susanna L Cardell
- Department of Microbiology and Immunology, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg , Gothenburg , Sweden
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Liang D, Nian H, Shao H, Kaplan HJ, Sun D. Functional Conversion and Dominance of γδ T Subset in Mouse Experimental Autoimmune Uveitis. THE JOURNAL OF IMMUNOLOGY 2017; 198:1429-1438. [PMID: 28069804 DOI: 10.4049/jimmunol.1601510] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/30/2016] [Accepted: 12/14/2016] [Indexed: 12/19/2022]
Abstract
We have previously shown that activated γδ T cells have a much stronger proinflammatory effect in the development of experimental autoimmune uveitis than their nonactivated counterparts. Our present study explored γδ T cell subsets are functionally distinct in autoimmune pathogenesis and determined the pathogenic contribution of biased Vγ4+ γδ T cell activation in this disease. By systematically comparing two major peripheral γδ T cell subsets, the Vγ1+ and the Vγ4+ cells, we found that the Vγ4+ cells were readily activated in B6 mice during experimental autoimmune uveitis development, whereas Vγ1+ cells remained nonactivated. Cytokines that were abundantly found in the serum of immunized mice activated Vγ4+, but did not activate Vγ1+, cells. The Vγ4+ cells had a strong proinflammatory activity, whereas the Vγ1+ cells remained nonactivated when tested immediately after isolation from immunized mice. However, when the Vγ1+ cells were activated in vitro, they promoted inflammation. Our results demonstrated that activation is a major factor in switching the enhancing and inhibiting effects of both Vγ1+ and Vγ4+ γδ T cell subsets, and that γδ T cell subsets differ greatly in their activation requirements. Whether the enhancing or inhibiting function of γδ T cells is dominant is mainly determined by the proportion of the γδ T cells that are activated versus the proportion not activated.
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Affiliation(s)
- Dongchun Liang
- Doheny Eye Institute, Department of Ophthalmology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90033
| | - Hong Nian
- Tianjin Medical University Eye Hospital, Eye Institute and School of Optometry and Ophthalmology, Tianjin 300384, China; and
| | - Hui Shao
- Department of Ophthalmology and Visual Sciences, Kentucky Lions Eye Center, University of Louisville, Louisville, KY 40202
| | - Henry J Kaplan
- Department of Ophthalmology and Visual Sciences, Kentucky Lions Eye Center, University of Louisville, Louisville, KY 40202
| | - Deming Sun
- Doheny Eye Institute, Department of Ophthalmology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90033;
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Abstract
Many rheumatic diseases are characterized by having an autoimmune background. Determining the mechanisms underlying autoimmunity is, therefore, important to further understand these diseases and to inform future lines of research aimed at developing new treatments and cures. As fast responders, innate lymphocytes have protective or pathogenic roles in the initiation as well as the maintenance of immune responses in general, and they contribute to tissue homeostasis, among other functions. Innate lymphocytes also seem to be involved in autoimmunity in particular. Since 2010, accumulating evidence clearly shows that different populations of innate lymphocytes have roles in responding to antigen-specific autoantibody and autoreactive T cells, thereby amplifying or attenuating disease processes. Cytotoxicity is a cardinal feature of many innate lymphocytes and can contribute to inflammatory tissue damage. Finally, innate lymphocytes can respond to biologic therapies for autoimmune diseases. Consequently, like TNF and other effector molecules, certain innate lymphocyte subsets might be appropriate therapeutic targets to ameliorate various autoimmune diseases. In this Review, we summarize the main characteristics and functions of innate lymphocyte subsets, and describe their roles in autoimmune disease. We also discuss how biologic therapies influence innate lymphocyte function and consider the potential for these cell subsets to act as future therapeutic targets.
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Malik S, Want MY, Awasthi A. The Emerging Roles of Gamma-Delta T Cells in Tissue Inflammation in Experimental Autoimmune Encephalomyelitis. Front Immunol 2016; 7:14. [PMID: 26858718 PMCID: PMC4731487 DOI: 10.3389/fimmu.2016.00014] [Citation(s) in RCA: 43] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2015] [Accepted: 01/12/2016] [Indexed: 12/13/2022] Open
Abstract
γδ (gamma–delta) T cells, a small population of unconventional T cells, have been found in central nervous system lesions of multiple sclerosis (MS) patients, but their function in disease activity is not clearly understood. Previous studies in experimental autoimmune encephalomyelitis (EAE) were inconsistent in identifying their specific roles in suppressing or promoting disease pathogenesis. Emerging advancements in the biology of γδ T cells especially in the context of their being the major initial producers of IL-17, suggested their crucial role in pathogenesis of EAE. In addition, γδ T cells express high levels of IL-23R and IL-1R, which further enhance their effector functions in the pathogenesis of EAE. Nonetheless, activated heterogeneous γδ T cells display functional dichotomy, which is crucial in determining the outcomes of tissue inflammation in EAE. In this review, we discussed recent advances in understanding the biology of γδ T cells in tissue inflammation as well as their roles in suppressing or promoting the development of EAE.
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Affiliation(s)
- Sakshi Malik
- Translational Health Science and Technology Institute , Faridabad , India
| | - Muzamil Yaqub Want
- Translational Health Science and Technology Institute , Faridabad , India
| | - Amit Awasthi
- Translational Health Science and Technology Institute , Faridabad , India
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Banerjee D, Zhao L, Wu L, Palanichamy A, Ergun A, Peng L, Quigley C, Hamann S, Dunstan R, Cullen P, Allaire N, Guertin K, Wang T, Chao J, Loh C, Fontenot JD. Small molecule mediated inhibition of RORγ-dependent gene expression and autoimmune disease pathology in vivo. Immunology 2016; 147:399-413. [PMID: 26694902 DOI: 10.1111/imm.12570] [Citation(s) in RCA: 43] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2015] [Revised: 12/16/2015] [Accepted: 12/17/2015] [Indexed: 12/14/2022] Open
Abstract
Retinoic acid receptor-related orphan nuclear receptor γ (RORγ) orchestrates a pro-inflammatory gene expression programme in multiple lymphocyte lineages including T helper type 17 (Th17) cells, γδ T cells, innate lymphoid cells and lymphoid tissue inducer cells. There is compelling evidence that RORγ-expressing cells are relevant targets for therapeutic intervention in the treatment of autoimmune and inflammatory diseases. Unlike Th17 cells, where RORγ expression is induced under specific pro-inflammatory conditions, γδ T cells and other innate-like immune cells express RORγ in the steady state. Small molecule mediated disruption of RORγ function in cells with pre-existing RORγ transcriptional complexes represents a significant and challenging pharmacological hurdle. We present data demonstrating that a novel, selective and potent small molecule RORγ inhibitor can block the RORγ-dependent gene expression programme in both Th17 cells and RORγ-expressing γδ T cells as well as a disease-relevant subset of human RORγ-expressing memory T cells. Importantly, systemic administration of this inhibitor in vivo limits pathology in an innate lymphocyte-driven mouse model of psoriasis.
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Affiliation(s)
| | - Linlin Zhao
- Immunology Research, Biogen, Cambridge, MA, USA
| | - Lan Wu
- Immunology Research, Biogen, Cambridge, MA, USA
| | | | - Ayla Ergun
- Translational Sciences - Genetics & Genomics, Biogen, Cambridge, MA, USA
| | | | | | - Stefan Hamann
- Translational Sciences - Pathology, Biogen, Cambridge, MA, USA
| | - Robert Dunstan
- Translational Sciences - Pathology, Biogen, Cambridge, MA, USA
| | - Patrick Cullen
- Translational Sciences - Genetics & Genomics, Biogen, Cambridge, MA, USA
| | - Norm Allaire
- Translational Sciences - Genetics & Genomics, Biogen, Cambridge, MA, USA
| | | | - Tao Wang
- Medicinal Chemistry, Biogen, Cambridge, MA, USA
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Hohlfeld R, Dornmair K, Meinl E, Wekerle H. The search for the target antigens of multiple sclerosis, part 2: CD8+ T cells, B cells, and antibodies in the focus of reverse-translational research. Lancet Neurol 2015; 15:317-31. [PMID: 26724102 DOI: 10.1016/s1474-4422(15)00313-0] [Citation(s) in RCA: 143] [Impact Index Per Article: 14.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2015] [Revised: 10/13/2015] [Accepted: 10/22/2015] [Indexed: 01/16/2023]
Abstract
Interest in CD8+ T cells and B cells was initially inspired by observations in multiple sclerosis rather than in animal models: CD8+ T cells predominate in multiple sclerosis lesions, oligoclonal immunoglobulin bands in CSF have long been recognised as diagnostic and prognostic markers, and anti-B-cell therapies showed considerable efficacy in multiple sclerosis. Taking a reverse-translational approach, findings from human T-cell receptor (TCR) and B-cell receptor (BCR) repertoire studies provided strong evidence for antigen-driven clonal expansion in the brain and CSF. New methods allow the reconstruction of human TCRs and antibodies from tissue-infiltrating immune cells, which can be used for the unbiased screening of antigen libraries. Myelin oligodendrocyte glycoprotein (MOG) has received renewed attention as an antibody target in childhood multiple sclerosis and in a small subgroup of adult patients with multiple sclerosis. Furthermore, there is growing evidence that a separate condition in adults exists, tentatively called MOG-antibody-associated encephalomyelitis, which has clinical features that overlap with neuromyelitis optica spectrum disorder and multiple sclerosis. Although CD8+ T cells and B cells are thought to have a pathogenic role in some subgroups of patients, their target antigens have yet to be identified.
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Affiliation(s)
- Reinhard Hohlfeld
- Institute of Clinical Neuroimmunology, Biomedical Center and University Hospital, Campus Martinsried-Grosshadern, Ludwig-Maximilians University, Munich, Germany; Munich Cluster of Systems Neurology (SyNergy), Munich, Germany.
| | - Klaus Dornmair
- Institute of Clinical Neuroimmunology, Biomedical Center and University Hospital, Campus Martinsried-Grosshadern, Ludwig-Maximilians University, Munich, Germany
| | - Edgar Meinl
- Institute of Clinical Neuroimmunology, Biomedical Center and University Hospital, Campus Martinsried-Grosshadern, Ludwig-Maximilians University, Munich, Germany
| | - Hartmut Wekerle
- HERTIE Senior Professor Group Neuroimmunology, Max Planck Institute of Neurobiology, Martinsried, Germany
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Macchi B, Marino-Merlo F, Nocentini U, Pisani V, Cuzzocrea S, Grelli S, Mastino A. Role of inflammation and apoptosis in multiple sclerosis: Comparative analysis between the periphery and the central nervous system. J Neuroimmunol 2015; 287:80-7. [PMID: 26439966 DOI: 10.1016/j.jneuroim.2015.08.016] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2015] [Revised: 08/19/2015] [Accepted: 08/24/2015] [Indexed: 01/23/2023]
Abstract
Multiple sclerosis (MS) is a complex, multifactorial disease associated with damage to the axonal myelin sheaths and neuronal degeneration. The pathognomonic event in MS is oligodendrocyte loss accompanied by axonal damage, blood-brain barrier leakage, inflammation and infiltration of immune cells. The etiopathogenesis of MS is far from being elucidated. However, increasing evidence suggests that the inflammatory and apoptotic responses, occurring in patients either at the peripheral level or the central nervous system (CNS), can play a role. In this review, we give a comprehensive picture of general aspects of inflammation and apoptosis in MS, with special emphasis on the until now not well highlighted possible links between phenomena relevant to these aspects occurring in either the periphery or in the CNS during MS.
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Affiliation(s)
- Beatrice Macchi
- Department of Systems Medicine, University of Rome "Tor Vergata", Via Montpellier 1, 00133 Rome, Italy.
| | - Francesca Marino-Merlo
- Department of Biological and Environmental Sciences, University of Messina, Via F. Stagno d'Alcontres 31, 98166 Messina, Italy.
| | - Ugo Nocentini
- Department of Systems Medicine, University of Rome "Tor Vergata", Via Montpellier 1, 00133 Rome, Italy; I.R.C.C.S. "Santa Lucia" Foundation, Via Ardeatina 306, 00179 Rome, Italy.
| | - Valerio Pisani
- I.R.C.C.S. "Santa Lucia" Foundation, Via Ardeatina 306, 00179 Rome, Italy.
| | - Salvatore Cuzzocrea
- Department of Biological and Environmental Sciences, University of Messina, Via F. Stagno d'Alcontres 31, 98166 Messina, Italy.
| | - Sandro Grelli
- Department of Experimental Medicine and Surgery, University of Rome "Tor Vergata", Via Montpellier 1, 00133 Rome, Italy.
| | - Antonio Mastino
- Department of Biological and Environmental Sciences, University of Messina, Via F. Stagno d'Alcontres 31, 98166 Messina, Italy; The Institute of Translational Pharmacology, CNR, Via Fosso del Cavaliere 100, 00133 Rome, Italy.
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Sato S, Yamamoto K, Matsushita T, Isobe N, Kawano Y, Iinuma K, Niino M, Fukazawa T, Nakamura Y, Watanabe M, Yonekawa T, Masaki K, Yoshimura S, Murai H, Yamasaki R, Kira JI. Copy number variations in multiple sclerosis and neuromyelitis optica. Ann Neurol 2015; 78:762-74. [PMID: 26296936 DOI: 10.1002/ana.24511] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2015] [Revised: 08/19/2015] [Accepted: 08/19/2015] [Indexed: 12/30/2022]
Abstract
OBJECTIVE To clarify the potential association of copy number variations (CNVs) with multiple sclerosis (MS) and neuromyelitis optica (NMO) in Japanese cases. METHODS Genome-wide association analyses of CNVs among 277 MS patients, 135 NMO/NMO spectrum disorder (NMOSD) patients, and 288 healthy individuals as a discovery cohort, and among 296 MS patients, 76 NMO/NMOSD patients, and 790 healthy individuals as a replication cohort were performed using high-density single nucleotide polymorphism microarrays. RESULTS A series of discovery and replication studies revealed that most identified CNVs were 5 to 50kb deletions at particular T cell receptor (TCR) gamma and alpha loci regions. Among these CNVs, a TCR gamma locus deletion was found in 16.40% of MS patients (p = 2.44E-40, odds ratio [OR] = 52.6), and deletion at the TCR alpha locus was found in 17.28% of MS patients (p = 1.70E-31, OR = 13.0) and 13.27% of NMO/NMOSD patients (p = 5.79E-20, OR = 54.6). These CNVs were observed in peripheral blood T-cell subsets only, suggesting the CNVs were somatically acquired. NMO/NMOSD patients carrying the CNV tended to be seronegative for anti-aquaporin-4 antibody or had significantly lower titers than those without CNV. INTERPRETATION Deletion-type CNVs at specific TCR loci regions contribute to MS and NMO susceptibility.
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Affiliation(s)
- Shinya Sato
- Department of Neurology, Neurological Institute, Graduate School of Medical Sciences, Kyushu University, Fukuoka
| | - Ken Yamamoto
- Department of Medical Chemistry, Kurume University School of Medicine, Kurume
| | - Takuya Matsushita
- Department of Neurological Therapeutics, Neurological Institute, Graduate School of Medical Sciences, Kyushu University, Fukuoka
| | - Noriko Isobe
- Department of Neurology, Neurological Institute, Graduate School of Medical Sciences, Kyushu University, Fukuoka
| | - Yuji Kawano
- Department of Neurology, Neurological Institute, Graduate School of Medical Sciences, Kyushu University, Fukuoka
| | - Kyoko Iinuma
- Department of Neurology, Neurological Institute, Graduate School of Medical Sciences, Kyushu University, Fukuoka
| | - Masaaki Niino
- Department of Clinical Research, Hokkaido Medical Center, Hokkaido
| | | | - Yuri Nakamura
- Department of Neurology, Neurological Institute, Graduate School of Medical Sciences, Kyushu University, Fukuoka
| | - Mitsuru Watanabe
- Department of Neurology, Neurological Institute, Graduate School of Medical Sciences, Kyushu University, Fukuoka
| | - Tomomi Yonekawa
- Department of Neurology, Neurological Institute, Graduate School of Medical Sciences, Kyushu University, Fukuoka
| | - Katsuhisa Masaki
- Department of Neurology, Neurological Institute, Graduate School of Medical Sciences, Kyushu University, Fukuoka
| | - Satoshi Yoshimura
- Department of Neurology, Neurological Institute, Graduate School of Medical Sciences, Kyushu University, Fukuoka
| | - Hiroyuki Murai
- Department of Neurology, Neurological Institute, Graduate School of Medical Sciences, Kyushu University, Fukuoka
| | - Ryo Yamasaki
- Department of Neurological Therapeutics, Neurological Institute, Graduate School of Medical Sciences, Kyushu University, Fukuoka
| | - Jun-Ichi Kira
- Department of Neurology, Neurological Institute, Graduate School of Medical Sciences, Kyushu University, Fukuoka
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Edwards SC, McGinley AM, McGuinness NC, Mills KHG. γδ T Cells and NK Cells - Distinct Pathogenic Roles as Innate-Like Immune Cells in CNS Autoimmunity. Front Immunol 2015; 6:455. [PMID: 26441960 PMCID: PMC4561808 DOI: 10.3389/fimmu.2015.00455] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2015] [Accepted: 08/24/2015] [Indexed: 12/31/2022] Open
Affiliation(s)
- Sarah C Edwards
- Immune Regulation Research Group, Trinity Biomedical Sciences Institute, School of Biochemistry and Immunology, Trinity College Dublin , Dublin , Ireland
| | - Aoife M McGinley
- Immune Regulation Research Group, Trinity Biomedical Sciences Institute, School of Biochemistry and Immunology, Trinity College Dublin , Dublin , Ireland
| | - Niamh C McGuinness
- Immune Regulation Research Group, Trinity Biomedical Sciences Institute, School of Biochemistry and Immunology, Trinity College Dublin , Dublin , Ireland ; Trinity College Institute of Neuroscience, Trinity College Dublin , Dublin , Ireland
| | - Kingston H G Mills
- Immune Regulation Research Group, Trinity Biomedical Sciences Institute, School of Biochemistry and Immunology, Trinity College Dublin , Dublin , Ireland
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Derkow K, Krüger C, Dembny P, Lehnardt S. Microglia Induce Neurotoxic IL-17+ γδ T Cells Dependent on TLR2, TLR4, and TLR9 Activation. PLoS One 2015; 10:e0135898. [PMID: 26288016 PMCID: PMC4545749 DOI: 10.1371/journal.pone.0135898] [Citation(s) in RCA: 47] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2015] [Accepted: 07/28/2015] [Indexed: 11/29/2022] Open
Abstract
Background Interleukin-17 (IL-17) acts as a key regulator in central nervous system (CNS) inflammation. γδ T cells are an important innate source of IL-17. Both IL-17+ γδ T cells and microglia, the major resident immune cells of the brain, are involved in various CNS disorders such as multiple sclerosis and stroke. Also, activation of Toll-like receptor (TLR) signaling pathways contributes to CNS damage. However, the mechanisms underlying the regulation and interaction of these cellular and molecular components remain unclear. Objective In this study, we investigated the crosstalk between γδ T cells and microglia activated by TLRs in the context of neuronal damage. To this end, co-cultures of IL-17+ γδ T cells, neurons, and microglia were analyzed by immunocytochemistry, flow cytometry, ELISA and multiplex immunoassays. Results We report here that IL-17+ γδ T cells but not naïve γδ T cells induce a dose- and time-dependent decrease of neuronal viability in vitro. While direct stimulation of γδ T cells with various TLR ligands did not result in up-regulation of CD69, CD25, or in IL-17 secretion, supernatants of microglia stimulated by ligands specific for TLR2, TLR4, TLR7, or TLR9 induced activation of γδ T cells through IL-1β and IL-23, as indicated by up-regulation of CD69 and CD25 and by secretion of vast amounts of IL-17. This effect was dependent on the TLR adaptor myeloid differentiation primary response gene 88 (MyD88) expressed by both γδ T cells and microglia, but did not require the expression of TLRs by γδ T cells. Similarly to cytokine-primed IL-17+ γδ T cells, IL-17+ γδ T cells induced by supernatants derived from TLR-activated microglia also caused neurotoxicity in vitro. While these neurotoxic effects required stimulation of TLR2, TLR4, or TLR9 in microglia, neuronal injury mediated by bone marrow-derived macrophages did not require TLR signaling. Neurotoxicity mediated by IL-17+ γδ T cells required a direct cell-cell contact between T cells and neurons. Conclusion Taken together, these results point to a crucial role for microglia activated through TLRs in polarization of γδ T cells towards neurotoxic IL-17+ γδ T cells.
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Affiliation(s)
- Katja Derkow
- Department of Neurology, Charité - Universitaetsmedizin Berlin, Berlin, Germany
| | - Christina Krüger
- Department of Neurology, Charité - Universitaetsmedizin Berlin, Berlin, Germany
| | - Paul Dembny
- Department of Neurology, Charité - Universitaetsmedizin Berlin, Berlin, Germany
| | - Seija Lehnardt
- Department of Neurology, Charité - Universitaetsmedizin Berlin, Berlin, Germany; Cluster of Excellence NeuroCure, Charité - Universitaetsmedizin Berlin, Berlin, Germany; Institute of Cell Biology and Neurobiology, Center for Anatomy, Charité - Universitaetsmedizin Berlin, Berlin, Germany
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45
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Pauza CD, Cairo C. Evolution and function of the TCR Vgamma9 chain repertoire: It's good to be public. Cell Immunol 2015; 296:22-30. [PMID: 25769734 PMCID: PMC4466227 DOI: 10.1016/j.cellimm.2015.02.010] [Citation(s) in RCA: 36] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2015] [Revised: 02/11/2015] [Accepted: 02/17/2015] [Indexed: 01/17/2023]
Abstract
Lymphocytes expressing a T cell receptor (TCR) composed of Vgamma9 and Vdelta2 chains represent a minor fraction of human thymocytes. Extrathymic selection throughout post-natal life causes the proportion of cells with a Vgamma9-JP rearrangement to increase and elevates the capacity for responding to non-peptidic phosphoantigens. Extrathymic selection is so powerful that phosphoantigen-reactive cells comprise about 1 in 40 circulating memory T cells in healthy adults and the subset expands rapidly upon infection or in response to malignancy. Skewing of the gamma delta TCR repertoire is accompanied by selection for public gamma chain sequences such that many unrelated individuals overlap extensive in their circulating repertoire. This type of selection implies the presence of a monomorphic antigen-presenting molecule that is an object of current research but remains incompletely defined. While selection on a monomorphic presenting molecule may seem unusual, similar mechanisms shape the alpha beta T cell repertoire including the extreme examples of NKT or mucosal-associated invariant T cells (MAIT) and the less dramatic amplification of public Vbeta chain rearrangements driven by individual MHC molecules and associated with resistance to viral pathogens. Selecting and amplifying public T cell receptors whether alpha beta or gamma delta, are important steps in developing an anticipatory TCR repertoire. Cell clones expressing public TCR can accelerate the kinetics of response to pathogens and impact host survival.
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MESH Headings
- Amino Acid Sequence
- Animals
- Base Sequence
- CD4-Positive T-Lymphocytes/immunology
- CD8-Positive T-Lymphocytes/immunology
- Evolution, Molecular
- Humans
- Immunologic Memory/immunology
- Natural Killer T-Cells/immunology
- Receptors, Antigen, T-Cell, alpha-beta/genetics
- Receptors, Antigen, T-Cell, alpha-beta/immunology
- Receptors, Antigen, T-Cell, gamma-delta/genetics
- Receptors, Antigen, T-Cell, gamma-delta/immunology
- Sequence Homology
- T-Lymphocyte Subsets/immunology
- Thymocytes/immunology
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Affiliation(s)
- C David Pauza
- Institute of Human Virology, University of Maryland School of Medicine, Baltimore, MD 21201, USA.
| | - Cristiana Cairo
- Institute of Human Virology, University of Maryland School of Medicine, Baltimore, MD 21201, USA
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46
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Hou L, Wang T, Sun J. γδ T cells in infection and autoimmunity. Int Immunopharmacol 2015; 28:887-91. [PMID: 25864620 DOI: 10.1016/j.intimp.2015.03.038] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2015] [Accepted: 03/28/2015] [Indexed: 01/13/2023]
Abstract
Standing at the interface of innate and adaptive immune, γδ T cells play important pathophysiologic roles in infection, autoimmunity, and tumorigenesis. Recent studies indicate that γδ T cells could be categorized into IFN-γ(+) and IL-17(+) subsets, both of which possess select TCR usages, bear unique surface markers and require different cytokine signaling to maintain the homeostasis. In addition, as the major innate IL-17 producers, γδ T cells are increasingly appreciated for their involvement in various acute infections and injuries. This review will summarize the characteristics of IFN-γ(+) (γδ T-IFN-γ) and IL-17(+) γδ T cells (γδT17) and discuss their distinct pathogenic functions in different disease models.
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Affiliation(s)
- Lifei Hou
- Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX 77555-1070, USA.
| | - Tian Wang
- Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX 77555-1070, USA
| | - Jiaren Sun
- Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX 77555-1070, USA.
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47
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Annexin A2 as a target endothelial cell membrane autoantigen in Behçet's disease. Sci Rep 2015; 5:8162. [PMID: 25641213 PMCID: PMC4313095 DOI: 10.1038/srep08162] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2014] [Accepted: 01/06/2015] [Indexed: 12/27/2022] Open
Abstract
Cell membrane proteins are believed to play a critical role in the pathogenesis of autoimmune diseases. However, few membrane autoantigens have been linked with Behçet's disease. Here, a cell-chip was performed to identify autoantibody target cells, and the suspected autoantigens were detected using immunoblotting. The amino acid sequences of the detected proteins were determined using LC-MALDI-TOF/TOF. Putative proteins were recombinantly expressed and purified, and a corresponding ELISA was developed and clinically validated using real clinical samples. It was found that a 36-kDa membrane protein--annexin A2--was detected in approximately one-third of the patients' blood circulation. The immunohistochemistry results showed that annexin A2 was highly expressed in vascular endothelial cells. Moreover, vascular involvement was significantly higher in the anti-annexin A2 antibody-positive group versus the anti-annexin A2 antibody-negative group among all the clinical samples analyzed, indicating that annexin A2 is a novel endothelial cell membrane antigen involved in Behçet's disease.
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48
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Positive or negative involvement of heat shock proteins in multiple sclerosis pathogenesis: an overview. J Neuropathol Exp Neurol 2015; 73:1092-106. [PMID: 25383635 DOI: 10.1097/nen.0000000000000136] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2023] Open
Abstract
Multiple sclerosis (MS) is the most diffuse chronic inflammatory disease of the central nervous system. Both immune-mediated and neurodegenerative processes apparently play roles in the pathogenesis of this disease. Heat shock proteins (HSPs) are a family of highly evolutionarily conserved proteins; their expression in the nervous system is induced in a variety of pathologic states, including cerebral ischemia, neurodegenerative diseases, epilepsy, and trauma. To date, investigators have observed protective effects of HSPs in a variety of brain disease models (e.g. of Alzheimer disease and Parkinson disease). In contrast, unequivocal data have been obtained for their roles in MS that depend on the HSP family and particularly on their localization (i.e. intracellular or extracellular). This article reviews our current understanding of the involvement of the principal HSP families in MS.
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Abstract
γδ T cells represent a small population of overall T lymphocytes (0.5-5%) and have variable tissue distribution in the body. γδ T cells can perform complex functions, such as immune surveillance, immunoregulation, and effector function, without undergoing clonal expansion. Heterogeneous distribution and anatomic localization of γδ T cells in the normal and inflamed tissues play an important role in alloimmunity, autoimmunity, or immunity. The cross-talk between γδ T cells and other immune cells and phenotypic and functional plasticity of γδ T cells have been given recent attention in the field of immunology. In this review, we discussed the cellular and molecular interaction of γδ T cells with other immune cells and its mechanism in the pathogenesis of various autoimmune diseases.
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Affiliation(s)
- Sourav Paul
- National Centre for Cell Science, Pune University Campus, Pune, India
| | - Shilpi
- National Centre for Cell Science, Pune University Campus, Pune, India
| | - Girdhari Lal
- National Centre for Cell Science, Pune University Campus, Pune, India
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Kumar V, Delovitch TL. Different subsets of natural killer T cells may vary in their roles in health and disease. Immunology 2014; 142:321-36. [PMID: 24428389 DOI: 10.1111/imm.12247] [Citation(s) in RCA: 77] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2013] [Revised: 01/08/2014] [Accepted: 01/08/2014] [Indexed: 12/31/2022] Open
Abstract
Natural killer T cells (NKT) can regulate innate and adaptive immune responses. Type I and type II NKT cell subsets recognize different lipid antigens presented by CD1d, an MHC class-I-like molecule. Most type I NKT cells express a semi-invariant T-cell receptor (TCR), but a major subset of type II NKT cells reactive to a self antigen sulphatide use an oligoclonal TCR. Whereas TCR-α dominates CD1d-lipid recognition by type I NKT cells, TCR-α and TCR-β contribute equally to CD1d-lipid recognition by type II NKT cells. These variable modes of NKT cell recognition of lipid-CD1d complexes activate a host of cytokine-dependent responses that can either exacerbate or protect from disease. Recent studies of chronic inflammatory and autoimmune diseases have led to a hypothesis that: (i) although type I NKT cells can promote pathogenic and regulatory responses, they are more frequently pathogenic, and (ii) type II NKT cells are predominantly inhibitory and protective from such responses and diseases. This review focuses on a further test of this hypothesis by the use of recently developed techniques, intravital imaging and mass cytometry, to analyse the molecular and cellular dynamics of type I and type II NKT cell antigen-presenting cell motility, interaction, activation and immunoregulation that promote immune responses leading to health versus disease outcomes.
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Affiliation(s)
- Vipin Kumar
- Laboratory of Autoimmunity, Torrey Pines Institute for Molecular Studies, San Diego, CA, USA
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