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Yang F, Li X, Wang J, Duan Z, Ren C, Guo P, Kong Y, Bi M, Zhang Y. Identification of lipid metabolism-related gene markers and construction of a diagnostic model for multiple sclerosis: An integrated analysis by bioinformatics and machine learning. Anal Biochem 2025; 700:115781. [PMID: 39855613 DOI: 10.1016/j.ab.2025.115781] [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: 09/13/2024] [Revised: 12/20/2024] [Accepted: 01/20/2025] [Indexed: 01/27/2025]
Abstract
BACKGROUND Multiple sclerosis (MS) is an autoimmune inflammatory disorder that causes neurological disability. Dysregulated lipid metabolism contributes to the pathogenesis of MS. This study aimed to identify lipid metabolism-related gene markers and construct a diagnostic model for MS. METHODS Gene expression profiles for MS were obtained from the Gene Expression Omnibus database. Differentially expressed lipid metabolism-related genes (LMRGs) were identified and performed functional enrichment analysis. Least absolute shrinkage and selection operator (LASSO), random forest (RF), and protein-protein interaction (PPI) analysis were employed to screen hub genes. The predictive power of hub genes was evaluated using receiver operating characteristic (ROC) curves. We developed an artificial neural network (ANN) model and validated its performance in three test sets. Immune cell infiltration analysis, Gene set enrichment analysis, and ceRNA network construction were performed to explore the role of lipid metabolism in the pathogenesis of MS. Drugs prediction and molecular docking were utilized to identify potential therapeutic drugs. RESULTS We identified 40 differentially expressed LMRGs, with significant enrichment in Arachidonic acid metabolism, Steroid hormone biosynthesis, Fatty acid elongation, and Sphingolipid metabolism. AKR1C3, NFKB1, and ABCA1 were identified as gene markers for MS, and their expression was upregulated in the MS group. The areas under the ROC curve (AUCs) for AKR1C3, NFKB1, and ABCA1 in the training set were 0.779, 0.703, and 0.726, respectively. The ANN model exhibited good discriminative ability in both the training and test sets, achieving an AUC of 0.826 on the training set and AUC values of 0.822, 0.890, and 0.833 on the test sets. Gamma.delta.T.cell, Natural.killer.T.cell, Plasmacytoid.dendritic.cell, Regulatory.T.cell, and Type.1.T.helper.cell were highly expressed in the MS group. A ceRNA network showed a complex regulatory interplay involving hub genes. Luteolin, isoflavone, and thalidomide had good binding affinities to the hub genes. CONCLUSION Our study emphasized the crucial role of lipid metabolism in MS, identifing AKR1C3, NFKB1, and ABCA1 as gene markers. The ANN model exhibited good performance on both the training and testing sets. These findings offer valuable insights into the molecular mechanisms underlying MS, and establish a scientific foundation for future research.
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Affiliation(s)
- Fangjie Yang
- Rehabilitation Medicine College, Henan University of Chinese Medicine, Zhengzhou, Henan, China
| | - Xinmin Li
- School of Traditional Chinese Medicine, Henan University of Chinese Medicine, Zhengzhou, Henan, China
| | - Jing Wang
- Rehabilitation Medicine College, Henan University of Chinese Medicine, Zhengzhou, Henan, China
| | - Zhenfei Duan
- Rehabilitation Medicine College, Henan University of Chinese Medicine, Zhengzhou, Henan, China
| | - Chunlin Ren
- Rehabilitation Medicine College, Henan University of Chinese Medicine, Zhengzhou, Henan, China
| | - Pengxue Guo
- Rehabilitation Medicine College, Henan University of Chinese Medicine, Zhengzhou, Henan, China
| | - Yuting Kong
- Rehabilitation Medicine College, Henan University of Chinese Medicine, Zhengzhou, Henan, China
| | - Mengyao Bi
- Rehabilitation Medicine College, Henan University of Chinese Medicine, Zhengzhou, Henan, China
| | - Yasu Zhang
- Rehabilitation Medicine College, Henan University of Chinese Medicine, Zhengzhou, Henan, China.
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Li YR, Zhu Y, Chen Y, Yang L. The clinical landscape of CAR-engineered unconventional T cells. Trends Cancer 2025:S2405-8033(25)00069-X. [PMID: 40155286 DOI: 10.1016/j.trecan.2025.03.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2025] [Revised: 02/27/2025] [Accepted: 03/04/2025] [Indexed: 04/01/2025]
Abstract
Unconventional T cells, such as invariant natural killer T (iNKT), γδ T, and mucosal-associated invariant T (MAIT) cells, play a pivotal role in bridging innate and adaptive immunity. Their capacity for rapid tumor targeting and effective modulation of the tumor microenvironment (TME) makes them promising candidates for cancer immunotherapy. Advances in chimeric antigen receptor (CAR) engineering have further highlighted their therapeutic potential, particularly for treating challenging cancers. Notably, these cells exhibit favorable safety profiles, enhancing their viability as off-the-shelf therapeutic options. We provide a comprehensive analysis of the clinical applications of CAR-engineered unconventional T cells, focusing on genetic modifications, manufacturing processes, preconditioning regimens, and dosing strategies. We discuss successful examples from recent clinical trials and explore future directions for utilizing these cells in cancer therapy and beyond.
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Affiliation(s)
- Yan-Ruide Li
- Department of Microbiology, Immunology, and Molecular Genetics (MIMG), University of California Los Angeles, Los Angeles, CA 90095, USA; Department of Bioengineering, University of California Los Angeles, Los Angeles, CA 90095, USA.
| | - Yichen Zhu
- Department of Microbiology, Immunology, and Molecular Genetics (MIMG), University of California Los Angeles, Los Angeles, CA 90095, USA; Department of Bioengineering, University of California Los Angeles, Los Angeles, CA 90095, USA
| | - Yuning Chen
- Department of Microbiology, Immunology, and Molecular Genetics (MIMG), University of California Los Angeles, Los Angeles, CA 90095, USA; Department of Bioengineering, University of California Los Angeles, Los Angeles, CA 90095, USA
| | - Lili Yang
- Department of Microbiology, Immunology, and Molecular Genetics (MIMG), University of California Los Angeles, Los Angeles, CA 90095, USA; Department of Bioengineering, University of California Los Angeles, Los Angeles, CA 90095, USA; Molecular Biology Institute, University of California Los Angeles, Los Angeles, CA 90095, USA; Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, University of California Los Angeles, Los Angeles, CA 90095, USA; Jonsson Comprehensive Cancer Center, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA 90095, USA; Parker Institute for Cancer Immunotherapy, University of California Los Angeles, Los Angeles, CA 90095, USA.
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Yu J, Yang Y, Gu Z, Shi M, La Cava A, Liu A. CAR immunotherapy in autoimmune diseases: promises and challenges. Front Immunol 2024; 15:1461102. [PMID: 39411714 PMCID: PMC11473342 DOI: 10.3389/fimmu.2024.1461102] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2024] [Accepted: 08/30/2024] [Indexed: 10/19/2024] Open
Abstract
In recent years, the use of chimeric antigen receptor (CAR)-T cells has emerged as a promising immunotherapy in multiple diseases. CAR-T cells are T cells genetically modified to express a surface receptor, known as CAR, for the targeting of cognate antigens on specific cells. The effectiveness of CAR-T cell therapy in hematologic malignancies including leukemia, myeloma, and non-Hodgkin's lymphoma has led to consider its use as a potential avenue of treatment for autoimmune diseases. However, broadening the use of CAR-T cell therapy to a large spectrum of autoimmune conditions is challenging particularly because of the possible development of side effects including cytokine release syndrome and neurotoxicity. The design of CAR therapy that include additional immune cells such as double-negative T cells, γδ T cells, T regulatory cells and natural killer cells has shown promising results in preclinical studies and clinical trials in oncology, suggesting a similar potential utility in the treatment of autoimmune diseases. This review examines the mechanisms, efficacy, and safety of CAR approaches with a focus on their use in autoimmune diseases including systemic lupus erythematosus, Sjögren's syndrome, systemic sclerosis, multiple sclerosis, myasthenia gravis, lupus nephritis and other autoimmune diseases. Advantages and disadvantages as compared to CAR-T cell therapy will also be discussed.
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Affiliation(s)
- Jingjing Yu
- Hebei Medical University-National University of Ireland Galway Stem Cell Research Center, Hebei Medical University, Shijiazhuang, Hebei, China
| | - Yiming Yang
- Hebei Medical University-National University of Ireland Galway Stem Cell Research Center, Hebei Medical University, Shijiazhuang, Hebei, China
| | - Zhanjing Gu
- Hebei Medical University-National University of Ireland Galway Stem Cell Research Center, Hebei Medical University, Shijiazhuang, Hebei, China
| | - Min Shi
- Department of Clinical Laboratory, The Second Hospital of Hebei Medical University, Shijiazhuang, Hebei, China
- Hebei Key Laboratory of Laboratory Medicine, The Second Hospital of Hebei Medical University, Shijiazhuang, Hebei, China
| | - Antonio La Cava
- Department of Medicine, University of California Los Angeles, Los Angeles, CA, United States
- Department of Medicina Molecolare e Biotecnologie Mediche, Federico II University, Naples, Italy
| | - Aijing Liu
- Hebei Key Laboratory of Laboratory Medicine, The Second Hospital of Hebei Medical University, Shijiazhuang, Hebei, China
- Department of Rheumatology and Immunology, The Second Hospital of Hebei Medical University, Shijiazhuang, Hebei, China
- Hebei Research Center for Stem Cell Medical Translational Engineering, Shijiazhuang, Hebei, China
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Wyatt-Johnson SK, Afify R, Brutkiewicz RR. The immune system in neurological diseases: What innate-like T cells have to say. J Allergy Clin Immunol 2024; 153:913-923. [PMID: 38365015 PMCID: PMC10999338 DOI: 10.1016/j.jaci.2024.02.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2023] [Revised: 01/26/2024] [Accepted: 02/13/2024] [Indexed: 02/18/2024]
Abstract
The immune system classically consists of 2 lines of defense, innate and adaptive, both of which interact with one another effectively to protect us against any pathogenic threats. Importantly, there is a diverse subset of cells known as innate-like T cells that act as a bridge between the innate and adaptive immune systems and are pivotal players in eliciting inflammatory immune responses. A growing body of evidence has demonstrated the regulatory impact of these innate-like T cells in central nervous system (CNS) diseases and that such immune cells can traffic into the brain in multiple pathological conditions, which can be typically attributed to the breakdown of the blood-brain barrier. However, until now, it has been poorly understood whether innate-like T cells have direct protective or causative properties, particularly in CNS diseases. Therefore, in this review, our attention is focused on discussing the critical roles of 3 unique subsets of unconventional T cells, namely, natural killer T cells, γδ T cells, and mucosal-associated invariant T cells, in the context of CNS diseases, disorders, and injuries and how the interplay of these immune cells modulates CNS pathology, in an attempt to gain a better understanding of their complex functions.
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Affiliation(s)
- Season K Wyatt-Johnson
- Department of Microbiology and Immunology, Stark Neurosciences Research Institute, Indiana University School of Medicine, Indianapolis, Ind
| | - Reham Afify
- Department of Microbiology and Immunology, Stark Neurosciences Research Institute, Indiana University School of Medicine, Indianapolis, Ind
| | - Randy R Brutkiewicz
- Department of Microbiology and Immunology, Stark Neurosciences Research Institute, Indiana University School of Medicine, Indianapolis, Ind.
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Ruiz-Fernández I, Sánchez-Díaz R, Ortega-Sollero E, Martín P. Update on the role of T cells in cognitive impairment. Br J Pharmacol 2024; 181:799-815. [PMID: 37559406 DOI: 10.1111/bph.16214] [Citation(s) in RCA: 6] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2023] [Revised: 07/03/2023] [Accepted: 08/03/2023] [Indexed: 08/11/2023] Open
Abstract
The central nervous system (CNS) has long been considered an immune-privileged site, with minimal interaction between immune cells, particularly of the adaptive immune system. Previously, the presence of immune cells in this organ was primarily linked to events involving disruption of the blood-brain barrier (BBB) or inflammation. However, current research has shown that immune cells are found patrolling CNS under homeostatic conditions. Specifically, T cells of the adaptive immune system are able to cross the BBB and are associated with ageing and cognitive impairment. In addition, T-cell infiltration has been observed in pathological conditions, where inflammation correlates with poor prognosis. Despite ongoing research, the role of this population in the ageing brain under both physiological and pathological conditions is not yet fully understood. In this review, we provide an overview of the interactions between T cells and other immune and CNS parenchymal cells, and examine the molecular mechanisms by which these interactions may contribute to normal brain function and the scenarios in which disruption of these connections lead to cognitive impairment. A comprehensive understanding of the role of T cells in the ageing brain and the underlying molecular pathways under normal conditions could pave the way for new research to better understand brain disorders. LINKED ARTICLES: This article is part of a themed issue From Alzheimer's Disease to Vascular Dementia: Different Roads Leading to Cognitive Decline. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v181.6/issuetoc.
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Affiliation(s)
| | - Raquel Sánchez-Díaz
- Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain
- CIBER de Enfermedades Cardiovasculares (CIBER-CV), Madrid, Spain
| | | | - Pilar Martín
- Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain
- CIBER de Enfermedades Cardiovasculares (CIBER-CV), Madrid, Spain
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Sarkar SK, Willson AML, Jordan MA. The Plasticity of Immune Cell Response Complicates Dissecting the Underlying Pathology of Multiple Sclerosis. J Immunol Res 2024; 2024:5383099. [PMID: 38213874 PMCID: PMC10783990 DOI: 10.1155/2024/5383099] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2023] [Revised: 12/05/2023] [Accepted: 12/11/2023] [Indexed: 01/13/2024] Open
Abstract
Multiple sclerosis (MS) is a neurodegenerative autoimmune disease characterized by the destruction of the myelin sheath of the neuronal axon in the central nervous system. Many risk factors, including environmental, epigenetic, genetic, and lifestyle factors, are responsible for the development of MS. It has long been thought that only adaptive immune cells, especially autoreactive T cells, are responsible for the pathophysiology; however, recent evidence has indicated that innate immune cells are also highly involved in disease initiation and progression. Here, we compile the available data regarding the role immune cells play in MS, drawn from both human and animal research. While T and B lymphocytes, chiefly enhance MS pathology, regulatory T cells (Tregs) may serve a more protective role, as can B cells, depending on context and location. Cells chiefly involved in innate immunity, including macrophages, microglia, astrocytes, dendritic cells, natural killer (NK) cells, eosinophils, and mast cells, play varied roles. In addition, there is evidence regarding the involvement of innate-like immune cells, such as γδ T cells, NKT cells, MAIT cells, and innate-like B cells as crucial contributors to MS pathophysiology. It is unclear which of these cell subsets are involved in the onset or progression of disease or in protective mechanisms due to their plastic nature, which can change their properties and functions depending on microenvironmental exposure and the response of neural networks in damage control. This highlights the need for a multipronged approach, combining stringently designed clinical data with carefully controlled in vitro and in vivo research findings, to identify the underlying mechanisms so that more effective therapeutics can be developed.
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Affiliation(s)
- Sujan Kumar Sarkar
- Department of Anatomy, Histology and Physiology, Faculty of Animal Science and Veterinary Medicine, Sher-e-Bangla Agricultural University, Dhaka, Bangladesh
| | - Annie M. L. Willson
- Biomedical Sciences and Molecular Biology, CPHMVS, James Cook University, Townsville, Queensland 4811, Australia
| | - Margaret A. Jordan
- Biomedical Sciences and Molecular Biology, CPHMVS, James Cook University, Townsville, Queensland 4811, Australia
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Ju T, Jiang D, Zhong C, Zhang H, Huang Y, Zhu C, Yang S, Yan D. Characteristics of circulating immune cells in HBV-related acute-on-chronic liver failure following artificial liver treatment. BMC Immunol 2023; 24:47. [PMID: 38007423 PMCID: PMC10676598 DOI: 10.1186/s12865-023-00579-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2023] [Accepted: 10/19/2023] [Indexed: 11/27/2023] Open
Abstract
BACKGROUND AND AIM Liver failure, which is predominantly caused by hepatitis B (HBV) can be improved by an artificial liver support system (ALSS). This study investigated the phenotypic heterogeneity of immunocytes in patients with HBV-related acute-on-chronic liver failure (HBV-ACLF) before and after ALSS therapy. METHODS A total of 22 patients with HBV-ACLF who received ALSS therapy were included in the study. Patients with Grade I according to the ACLF Research Consortium score were considered to have improved. Demographic and laboratory data were collected and analyzed during hospitalization. Immunological features of peripheral blood in the patients before and after ALSS were detected by mass cytometry analyses. RESULTS In total, 12 patients improved and 10 patients did not. According to the immunological features data after ALSS, the proportion of circulating monocytes was significantly higher in non-improved patients, but there were fewer γδT cells compared with those in improved patients. Characterization of 37 cell clusters revealed that the frequency of effector CD8+ T (P = 0.003), CD4+ TCM (P = 0.033), CD4+ TEM (P = 0.039), and inhibitory natural killer (NK) cells (P = 0.029) decreased in HBV-ACLF patients after ALSS therapy. Sub group analyses after treatment showed that the improved patients had higher proportions of CD4+ TCM (P = 0.010), CD4+ TEM (P = 0.021), and γδT cells (P = 0.003) and a lower proportion of monocytes (P = 0.012) compared with the non-improved patients. CONCLUSIONS Changes in effector CD8+ T cells, effector and memory CD4+ T cells, and inhibitory NK cells are associated with ALSS treatment of HBV-ACLF. Moreover, monocytes and γδT cells exhibited the main differences when patients obtained different prognoses. The phenotypic heterogeneity of lymphocytes and monocytes may contribute to the prognosis of ALSS and future immunotherapy strategies.
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Affiliation(s)
- Tao Ju
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, 79 Qingchun Road, Hangzhou, 310003, China
| | - Daixi Jiang
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, 79 Qingchun Road, Hangzhou, 310003, China
| | - Chengli Zhong
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, 79 Qingchun Road, Hangzhou, 310003, China
| | - Huafen Zhang
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, 79 Qingchun Road, Hangzhou, 310003, China
| | - Yandi Huang
- Department of Laboratory Medicine, College of Medicine, The First Affiliated Hospital, Zhejiang University, Hangzhou, 310003, China
| | - Chunxia Zhu
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, 79 Qingchun Road, Hangzhou, 310003, China
| | - Shigui Yang
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, 79 Qingchun Road, Hangzhou, 310003, China.
| | - Dong Yan
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, 79 Qingchun Road, Hangzhou, 310003, China.
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Hu Y, Hu Q, Li Y, Lu L, Xiang Z, Yin Z, Kabelitz D, Wu Y. γδ T cells: origin and fate, subsets, diseases and immunotherapy. Signal Transduct Target Ther 2023; 8:434. [PMID: 37989744 PMCID: PMC10663641 DOI: 10.1038/s41392-023-01653-8] [Citation(s) in RCA: 101] [Impact Index Per Article: 50.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2023] [Revised: 09/07/2023] [Accepted: 09/12/2023] [Indexed: 11/23/2023] Open
Abstract
The intricacy of diseases, shaped by intrinsic processes like immune system exhaustion and hyperactivation, highlights the potential of immune renormalization as a promising strategy in disease treatment. In recent years, our primary focus has centered on γδ T cell-based immunotherapy, particularly pioneering the use of allogeneic Vδ2+ γδ T cells for treating late-stage solid tumors and tuberculosis patients. However, we recognize untapped potential and optimization opportunities to fully harness γδ T cell effector functions in immunotherapy. This review aims to thoroughly examine γδ T cell immunology and its role in diseases. Initially, we elucidate functional differences between γδ T cells and their αβ T cell counterparts. We also provide an overview of major milestones in γδ T cell research since their discovery in 1984. Furthermore, we delve into the intricate biological processes governing their origin, development, fate decisions, and T cell receptor (TCR) rearrangement within the thymus. By examining the mechanisms underlying the anti-tumor functions of distinct γδ T cell subtypes based on γδTCR structure or cytokine release, we emphasize the importance of accurate subtyping in understanding γδ T cell function. We also explore the microenvironment-dependent functions of γδ T cell subsets, particularly in infectious diseases, autoimmune conditions, hematological malignancies, and solid tumors. Finally, we propose future strategies for utilizing allogeneic γδ T cells in tumor immunotherapy. Through this comprehensive review, we aim to provide readers with a holistic understanding of the molecular fundamentals and translational research frontiers of γδ T cells, ultimately contributing to further advancements in harnessing the therapeutic potential of γδ T cells.
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Affiliation(s)
- Yi Hu
- Microbiology and Immunology Department, School of Medicine, Faculty of Medical Science, Jinan University, Guangzhou, Guangdong, 510632, China
| | - Qinglin Hu
- Microbiology and Immunology Department, School of Medicine, Faculty of Medical Science, Jinan University, Guangzhou, Guangdong, 510632, China
- Guangdong Provincial Key Laboratory of Tumour Interventional Diagnosis and Treatment, Zhuhai Institute of Translational Medicine, Zhuhai People's Hospital Affiliated with Jinan University, Jinan University, Zhuhai, Guangdong, 519000, China
| | - Yongsheng Li
- Department of Medical Oncology, Chongqing University Cancer Hospital, Chongqing, 400030, China
| | - Ligong Lu
- Guangdong Provincial Key Laboratory of Tumour Interventional Diagnosis and Treatment, Zhuhai Institute of Translational Medicine, Zhuhai People's Hospital Affiliated with Jinan University, Jinan University, Zhuhai, Guangdong, 519000, China
| | - Zheng Xiang
- Microbiology and Immunology Department, School of Medicine, Faculty of Medical Science, Jinan University, Guangzhou, Guangdong, 510632, China
| | - Zhinan Yin
- Biomedical Translational Research Institute, Jinan University, Guangzhou, Guangdong, 510632, China.
| | - Dieter Kabelitz
- Institute of Immunology, Christian-Albrechts-University Kiel, Kiel, Germany.
| | - Yangzhe Wu
- Guangdong Provincial Key Laboratory of Tumour Interventional Diagnosis and Treatment, Zhuhai Institute of Translational Medicine, Zhuhai People's Hospital Affiliated with Jinan University, Jinan University, Zhuhai, Guangdong, 519000, China.
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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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Human Vδ2 T Cells and Their Versatility for Immunotherapeutic Approaches. Cells 2022; 11:cells11223572. [PMID: 36429001 PMCID: PMC9688761 DOI: 10.3390/cells11223572] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2022] [Revised: 11/06/2022] [Accepted: 11/09/2022] [Indexed: 11/16/2022] Open
Abstract
Gamma/delta (γδ) T cells are innate-like immune effectors that are a critical component linking innate and adaptive immune responses. They are recognized for their contribution to tumor surveillance and fight against infectious diseases. γδ T cells are excellent candidates for cellular immunotherapy due to their unique properties to recognize and destroy tumors or infected cells. They do not depend on the recognition of a single antigen but rather a broad-spectrum of diverse ligands through expression of various cytotoxic receptors. In this manuscript, we review major characteristics of the most abundant circulating γδ subpopulation, Vδ2 T cells, their immunotherapeutic potential, recent advances in expansion protocols, their preclinical and clinical applications for several infectious diseases and malignancies, and how additional modulation could enhance their therapeutic potential.
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11
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Sanz M, Mann BT, Chitrakar A, Soriano-Sarabia N. Defying convention in the time of COVID-19: Insights into the role of γδ T cells. Front Immunol 2022; 13:819574. [PMID: 36032159 PMCID: PMC9403327 DOI: 10.3389/fimmu.2022.819574] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2021] [Accepted: 07/14/2022] [Indexed: 11/13/2022] Open
Abstract
Coronavirus disease 2019 (COVID-19) is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). COVID-19 is a complex disease which immune response can be more or less potent. In severe cases, patients might experience a cytokine storm that compromises their vital functions and impedes clearance of the infection. Gamma delta (γδ) T lymphocytes have a critical role initiating innate immunity and shaping adaptive immune responses, and they are recognized for their contribution to tumor surveillance, fighting infectious diseases, and autoimmunity. γδ T cells exist as both circulating T lymphocytes and as resident cells in different mucosal tissues, including the lungs and their critical role in other respiratory viral infections has been demonstrated. In the context of SARS-CoV-2 infection, γδ T cell responses are understudied. This review summarizes the findings on the antiviral role of γδ T cells in COVID-19, providing insight into how they may contribute to the control of infection in the mild/moderate clinical outcome.
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12
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Depletion of γδ T Cells Leads to Reduced Angiogenesis and Increased Infiltration of Inflammatory M1-like Macrophages in Ischemic Muscle Tissue. Cells 2022; 11:cells11091490. [PMID: 35563796 PMCID: PMC9102774 DOI: 10.3390/cells11091490] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2022] [Revised: 04/25/2022] [Accepted: 04/27/2022] [Indexed: 02/06/2023] Open
Abstract
γδ T cells, a small subset of T cells in blood, play a substantial role in influencing immunoregulatory and inflammatory processes. The functional impact of γδ T cells on angiogenesis in ischemic muscle tissue has never been reported and is the topic of the present work. Femoral artery ligation (FAL) was used to induce angiogenesis in the lower leg of γδ T cell depleted mice and wildtype and isotype antibody-treated control groups. Gastrocnemius muscle tissue was harvested 3 and 7 days after FAL and assessed using (immuno-)histological analyses. Hematoxylin and Eosin staining showed an increased area of tissue damage in γδ T cell depleted mice 7 days after FAL. Impaired angiogenesis was demonstrated by lower capillary to muscle fiber ratio and decreased number of proliferating endothelial cells (CD31+/BrdU+). γδ T cell depleted mice showed an increased number of total leukocytes (CD45+), neutrophils (MPO+) and neutrophil extracellular traps (NETs) (MPO+/CitH3+), without changes in the neutrophils to NETs ratio. Moreover, the depletion resulted in a higher macrophage count (DAPI/CD68+) caused by an increase in inflammatory M1-like macrophages (CD68+/MRC1−). Altogether, we show that depletion of γδ T cells leads to increased accumulation of leukocytes and M1-like macrophages, along with impaired angiogenesis.
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13
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Zang X, Chen S, Zhu J, Ma J, Zhai Y. The Emerging Role of Central and Peripheral Immune Systems in Neurodegenerative Diseases. Front Aging Neurosci 2022; 14:872134. [PMID: 35547626 PMCID: PMC9082639 DOI: 10.3389/fnagi.2022.872134] [Citation(s) in RCA: 42] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2022] [Accepted: 03/25/2022] [Indexed: 12/31/2022] Open
Abstract
For decades, it has been widely believed that the blood-brain barrier (BBB) provides an immune privileged environment in the central nervous system (CNS) by blocking peripheral immune cells and humoral immune factors. This view has been revised in recent years, with increasing evidence revealing that the peripheral immune system plays a critical role in regulating CNS homeostasis and disease. Neurodegenerative diseases are characterized by progressive dysfunction and the loss of neurons in the CNS. An increasing number of studies have focused on the role of the connection between the peripheral immune system and the CNS in neurodegenerative diseases. On the one hand, peripherally released cytokines can cross the BBB, cause direct neurotoxicity and contribute to the activation of microglia and astrocytes. On the other hand, peripheral immune cells can also infiltrate the brain and participate in the progression of neuroinflammatory and neurodegenerative diseases. Neurodegenerative diseases have a high morbidity and disability rate, yet there are no effective therapies to stop or reverse their progression. In recent years, neuroinflammation has received much attention as a therapeutic target for many neurodegenerative diseases. In this review, we highlight the emerging role of the peripheral and central immune systems in neurodegenerative diseases, as well as their interactions. A better understanding of the emerging role of the immune systems may improve therapeutic strategies for neurodegenerative diseases.
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Affiliation(s)
- Xin Zang
- Department of Infectious Disease, Shengjing Hospital of China Medical University, Shenyang, China
| | - Si Chen
- Department of Neurology, the Fourth Affiliated Hospital of China Medical University, Shenyang, China
| | - JunYao Zhu
- Department of Infectious Disease, Shengjing Hospital of China Medical University, Shenyang, China
| | - Junwen Ma
- Department of Infectious Disease, Shengjing Hospital of China Medical University, Shenyang, China
| | - Yongzhen Zhai
- Department of Infectious Disease, Shengjing Hospital of China Medical University, Shenyang, China
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14
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Shao H, Kaplan HJ, Sun D. Bidirectional Effect of IFN-γ on Th17 Responses in Experimental Autoimmune Uveitis. FRONTIERS IN OPHTHALMOLOGY 2022; 2:831084. [PMID: 36188211 PMCID: PMC9521044 DOI: 10.3389/fopht.2022.831084] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
Abstract
Pro- and ant-inflammatory effects of IFN-γ have been repeatedly found in various immune responses, including cancer and autoimmune diseases. In a previous study we showed that the timing of treatment determines the effect of adenosine-based immunotherapy. In this study we examined the role of IFN-γ in pathogenic Th17 responses in experimental autoimmune uveitis (EAU). We observed that IFN-γ has a bidirectional effect on Th17 responses, when tested both in vitro and in vivo. Anti-IFN-γ antibody inhibits Th17 responses when applied in the initial phase of the immune response; however, it enhances the Th17 response if administered in a later phase of EAU. In the current study we showed that IFN-γ is an important immunomodulatory molecule in γδ T cell activation, as well as in Th17 responses. These results should advance our understanding of the regulation of Th17 responses in autoimmunity.
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Affiliation(s)
- Hui Shao
- Department of Ophthalmology and Visual Sciences, Kentucky Lions Eye Center, University of Louisville, Louisville, KY, United States
| | - Henry J. Kaplan
- Department of Ophthalmology, Saint Louis University School of Medicine, Saint Louis, MO, United States
| | - Deming Sun
- Doheny Eye Institute and Department of Ophthalmology, David Geffen School of Medicine at University of California, Los Angeles, Los Angeles, CA, United States
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15
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Giri S, Lal G. Differentiation and functional plasticity of gamma-delta (γδ) T cells under homeostatic and disease conditions. Mol Immunol 2021; 136:138-149. [PMID: 34146759 DOI: 10.1016/j.molimm.2021.06.006] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2021] [Revised: 05/29/2021] [Accepted: 06/09/2021] [Indexed: 12/27/2022]
Abstract
Gamma-delta (γδ) T cells are a heterogeneous population of immune cells, which constitute <5% of total T cells in mice lymphoid tissue and human peripheral blood. However, they comprise a higher proportion of T cells in the epithelial and mucosal barrier, where they perform immune functions, help in tissue repair, and maintaining homeostasis. These tissues resident γδ T cells possess properties of innate and adaptive immune cells which enables them to perform a variety of functions during homeostasis and disease. Emerging data suggest the involvement of γδ T cells during transplant rejection and survival. Interestingly, several functions of γδ T cells can be modulated through their interaction with other immune cells. This review provides an overview of development, differentiation plasticity into regulatory and effector phenotypes of γδ T cells during homeostasis and various diseases.
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Affiliation(s)
- Shilpi Giri
- National Centre for Cell Science, NCCS Complex, SP Pune University Campus, Ganeshkhind, Pune, MH-411007, India
| | - Girdhari Lal
- National Centre for Cell Science, NCCS Complex, SP Pune University Campus, Ganeshkhind, Pune, MH-411007, India.
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16
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Li Y, Zhang Y, Zeng X. γδ T Cells Participating in Nervous Systems: A Story of Jekyll and Hyde. Front Immunol 2021; 12:656097. [PMID: 33868300 PMCID: PMC8044362 DOI: 10.3389/fimmu.2021.656097] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2021] [Accepted: 03/15/2021] [Indexed: 11/18/2022] Open
Abstract
γδ T cells are distributed in various lymphoid and nonlymphoid tissues, and act as early responders in many conditions. Previous studies have proven their significant roles in infection, cancer, autoimmune diseases and tissue maintenance. Recently, accumulating researches have highlighted the crosstalk between γδ T cells and nervous systems. In these reports, γδ T cells maintain some physiological functions of central nervous system by secreting interleukin (IL) 17, and neurons like nociceptors can in turn regulate the activity of γδ T cells. Moreover, γδ T cells are involved in neuroinflammation such as stroke and multiple sclerosis. This review illustrates the relationship between γδ T cells and nervous systems in physiological and pathological conditions.
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Affiliation(s)
| | | | - Xun Zeng
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
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17
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Möhn N, Bruni E, Schröder A, Frömmel S, Gueler F, Vieten G, Prinz I, Kuebler JF, Petersen C, Klemann C. Synthetic retinoid AM80 inhibits IL-17 production of gamma delta T cells and ameliorates biliary atresia in mice. Liver Int 2020; 40:3031-3041. [PMID: 33463083 DOI: 10.1111/liv.14639] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/29/2020] [Revised: 08/03/2020] [Accepted: 08/10/2020] [Indexed: 12/26/2022]
Abstract
BACKGROUND & AIMS Recent evidence suggests that Interleukin (IL)-17-producing gamma delta ( γδ ) T cells are the dominant pathogenic cellular component in designated autoimmune or inflammatory diseases, including biliary atresia (BA). We have previously demonstrated that retinoids effectively suppress T-helper cell (Th) 17 differentiation. METHODS Here, we established an in vitro system, enabling investigations of the effect of AM80 on the IL-17 production of γδ T cells. Additionally, we tested the therapeutic effect of AM80 in the Rotavirus-induced mouse model of BA. Co-incubation of γδ T cells with IL-23 and anti-CD28 mAb proved most effective in inducing an IL-17 response in vitro. The effect of AM80 on human CCR6+CD26+ V δ 2 cells was assessed by flow cytometry. RESULTS AM80 efficiently reduced IL-17 production by murine γδ T cells and the expression of the master transcription factor Retinoid-Orphan-Receptor- γ t (ROR γτ ) in a dose-dependent manner. The fraction of human CCR6+CD26+ V δ 2 cells was significantly reduced by co-incubation with AM80. Moreover, AM80 also inhibited IL-17 production by liver-infiltrating γδ T cells isolated from animals suffering from BA. Intraperitoneal treatment with AM80 ameliorated BA-associated inflammation. However, AM80 treatment was not sufficient to control disease progression in the murine model, despite reduced inflammatory activity in the animals. CONCLUSIONS Retinoids are very efficient in down-regulating IL-17 production by γδ T cells in vitro and, to a lesser extent, in the BA mouse model. However, retinoids do not suffice for the control of disease progression. Thus, our data suggest that IL-17 is not the only factor contributing to the pathogenesis of BA. LAY SUMMARY Biliary atresia (BA) is a rare disease which affects infants, causing progressive liver failure in most children, and is the most common indication for paediatric liver transplantation. We have previously demonstrated that IL-17, produced by γδ T cells, contributes to hepatic inflammation in the murine model of BA and is increased in the livers of infants suffering from the disease. In the study at hand, we demonstrate that treatment with AM80, a synthetic retinoid with superior pharmacological properties, effectively inhibits the IL-17 production of gamma delta T cells without generating systemic immunosuppression. Although all-trans retinoic acid (ATRA) has been demonstrated to suppress differentiation of IL-17-producing conventional T-helper cells (Th17) in vitro, the therapeutic application of ATRA in vivo is limited by the compound's potential side effects caused by its instability and lack of receptor specificity. Our study is the first to show that AM80 suppresses the IL-17 production of γδ T cells in a very efficient manner and that hepatic inflammation is ameliorated in mice suffering from BA. However, AM80 treatment does not suffice to block the disease progression. We conclude that factors other than IL-17 drive the progressive inflammation in BA. The addition of retinoids to the treatment regime of children suffering from BA might decrease the disease burden; however, further research is needed to clarify the pathomechanism and possible therapeutic interventions in humans.
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Affiliation(s)
- Nora Möhn
- Department of Pediatric Surgery, Hannover Medical School, Hannover, Germany
| | - Elena Bruni
- Institute of Immunology, Hannover Medical School, Hannover, Germany
| | - Arne Schröder
- Department of Pediatric Surgery, Hannover Medical School, Hannover, Germany
| | - Stephanie Frömmel
- Department of Pediatric Surgery, Hannover Medical School, Hannover, Germany
| | - Faikah Gueler
- Department of Nephrology, Hannover Medical School, Hannover, Germany
| | - Gertrud Vieten
- Department of Pediatric Surgery, Hannover Medical School, Hannover, Germany
| | - Immo Prinz
- Institute of Immunology, Hannover Medical School, Hannover, Germany
| | - Joachim F Kuebler
- Department of Pediatric Surgery, Hannover Medical School, Hannover, Germany
| | - Claus Petersen
- Department of Pediatric Surgery, Hannover Medical School, Hannover, Germany
| | - Christian Klemann
- Department of Pediatric Surgery, Hannover Medical School, Hannover, Germany.,Department of Pediatric Pulmonology, Allergy and Neonatology, Hannover Medical School, Hannover, Germany
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18
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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: 49] [Impact Index Per Article: 9.8] [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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19
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Zhou QH, Wu FT, Pang LT, Zhang TB, Chen Z. Role of γδT cells in liver diseases and its relationship with intestinal microbiota. World J Gastroenterol 2020; 26:2559-2569. [PMID: 32523311 PMCID: PMC7265152 DOI: 10.3748/wjg.v26.i20.2559] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/10/2020] [Revised: 04/19/2020] [Accepted: 04/28/2020] [Indexed: 02/06/2023] Open
Abstract
γδT cells are unconventional T lymphocytes that bridge innate and adaptive immunity. Based on the composition of T cell receptor and the cytokines produced, γδT cells can be divided into diverse subsets that may be present at different locations, including the liver, epithelial layer of the gut, the dermis and so on. Many of these cells perform specific functions in liver diseases, such as viral hepatitis, autoimmune liver diseases, non-alcoholic fatty liver disease, liver cirrhosis and liver cancers. In this review, we discuss the distribution, subsets, functions of γδT cells and the relationship between the microbiota and γδT cells in common hepatic diseases. As γδT cells have been used to cure hematological and solid tumors, we are interested in γδT cell-based immunotherapies to treat liver diseases.
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Affiliation(s)
- Qi-Hui Zhou
- Department of Infectious Diseases, State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, the First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310000, Zhejiang Province, China
| | - Feng-Tian Wu
- Department of Infectious Diseases, State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, the First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310000, Zhejiang Province, China
| | - Lan-Tian Pang
- Department of Infectious Diseases, State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, the First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310000, Zhejiang Province, China
| | - Tian-Bao Zhang
- Department of Infectious Diseases, State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, the First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310000, Zhejiang Province, China
| | - Zhi Chen
- Department of Infectious Diseases, State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, the First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310000, Zhejiang Province, China
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20
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Mann BT, Sambrano E, Maggirwar SB, Soriano-Sarabia N. Boosting the Immune System for HIV Cure: A γδ T Cell Perspective. Front Cell Infect Microbiol 2020; 10:221. [PMID: 32509594 PMCID: PMC7248175 DOI: 10.3389/fcimb.2020.00221] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2020] [Accepted: 04/22/2020] [Indexed: 12/20/2022] Open
Abstract
The major barrier to HIV cure is a population of long-lived cells that harbor latent but replication-competent virus, are not eliminated by antiretroviral therapy (ART), and remain indistinguishable from uninfected cells. However, ART does not cure HIV infection, side effects to treatment still occur, and the steady global rate of new infections makes finding a sustained ART-free HIV remission or cure for HIV-seropositive individuals urgently needed. Approaches aimed to cure HIV are mostly based on the "shock and kill" method that entails the use of a drug compound to reactivate latent virus paired together with strategies to boost or supplement the existing immune system to clear reactivated latently infected cells. Traditionally, these strategies have utilized CD8+ cytotoxic lymphocytes (CTL) but have been met with a number of challenges. Enhancing innate immune cell populations, such as γδ T cells, may provide an alternative route to HIV cure. γδ T cells possess anti-viral and cytotoxic capabilities that have been shown to directly inhibit HIV infection and specifically eliminate reactivated, latently infected cells in vitro. Most notably, their access to immune privileged anatomical sites and MHC-independent antigen recognition may circumvent many of the challenges facing CTL-based strategies. In this review, we discuss the role of γδ T cells in normal immunity and HIV infection as well as their current use in strategies to treat cancer. We present this information as means to speculate about the utilization of γδ T cells for HIV cure strategies and highlight some of the fundamental gaps in knowledge that require investigation.
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Affiliation(s)
| | | | | | - Natalia Soriano-Sarabia
- Department of Microbiology, Immunology and Tropical Medicine, George Washington University, Washington, DC, United States
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21
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Zarobkiewicz MK, Kowalska W, Halczuk P, Woś J, Jodłowska-Jędrych B, Rejdak K, Roliński J, Bojarska-Junak AA. RORγT is overexpressed in iNKT and γδ T cells during relapse in relapsing-remitting multiple sclerosis. J Neuroimmunol 2019; 337:577046. [PMID: 31505409 DOI: 10.1016/j.jneuroim.2019.577046] [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: 04/16/2019] [Revised: 08/24/2019] [Accepted: 08/28/2019] [Indexed: 12/20/2022]
Abstract
The aim of the current study is to evaluate IL-17 production and RORγT, and IL-23R expression by iNKT, Th17 and γδ T cells in the peripheral blood of relapsing-remitting multiple sclerosis patients. Samples of peripheral blood from 21 relapse patients and 12 remission patients, and 15 healthy volunteers were stained with monoclonal antibodies for flow cytometry analysis. No significant differences in iNKT, γδ T and Th17 percentages were noted. The significant overexpression of RORγT was observed in all three subpopulations - therefore, iNKT, γδ T and Th cells may be an important source of IL-17 shortly prior to the relapse.
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Affiliation(s)
| | - Wioleta Kowalska
- Department of Clinical Immunology, Medical University of Lublin, Lublin, Poland
| | - Paweł Halczuk
- Department of Neurology, Medical University of Lublin, Lublin, Poland; Department of Histology and Embryology with Experimental Cytology Unit, Medical University of Lublin, Lublin, Poland
| | - Justyna Woś
- Department of Clinical Immunology, Medical University of Lublin, Lublin, Poland
| | - Barbara Jodłowska-Jędrych
- Department of Histology and Embryology with Experimental Cytology Unit, Medical University of Lublin, Lublin, Poland
| | - Konrad Rejdak
- Department of Neurology, Medical University of Lublin, Lublin, Poland
| | - Jacek Roliński
- Department of Clinical Immunology, Medical University of Lublin, Lublin, Poland
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22
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Kustrimovic N, Marino F, Cosentino M. Peripheral Immunity, Immunoaging and Neuroinflammation in Parkinson's Disease. Curr Med Chem 2019; 26:3719-3753. [PMID: 30306855 DOI: 10.2174/0929867325666181009161048] [Citation(s) in RCA: 34] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2017] [Revised: 06/26/2018] [Accepted: 09/12/2018] [Indexed: 12/20/2022]
Abstract
Parkinson's disease (PD) is the second most common neurodegenerative disorder among elderly population, characterized by the progressive degeneration of dopaminergic neurons in the midbrain. To date, exact cause remains unknown and the mechanism of neurons death uncertain. It is typically considered as a disease of central nervous system (CNS). Nevertheless, numerous evidence has been accumulated in several past years testifying undoubtedly about the principal role of neuroinflammation in progression of PD. Neuroinflammation is mainly associated with presence of activated microglia in brain and elevated levels of cytokine levels in CNS. Nevertheless, active participation of immune system as well has been noted, such as, elevated levels of cytokine levels in blood, the presence of auto antibodies, and the infiltration of T cell in CNS. Moreover, infiltration and reactivation of those T cells could exacerbate neuroinflammation to greater neurotoxic levels. Hence, peripheral inflammation is able to prime microglia into pro-inflammatory phenotype, which can trigger stronger response in CNS further perpetuating the on-going neurodegenerative process. In the present review, the interplay between neuroinflammation and the peripheral immune response in the pathobiology of PD will be discussed. First of all, an overview of regulation of microglial activation and neuroinflammation is summarized and discussed. Afterwards, we try to collectively analyze changes that occurs in peripheral immune system of PD patients, suggesting that these peripheral immune challenges can exacerbate the process of neuroinflammation and hence the symptoms of the disease. In the end, we summarize some of proposed immunotherapies for treatment of PD.
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Affiliation(s)
- Natasa Kustrimovic
- Center of Research in Medical Pharmacology, University of Insubria, Varese, Italy
| | - Franca Marino
- Center of Research in Medical Pharmacology, University of Insubria, Varese, Italy
| | - Marco Cosentino
- Center of Research in Medical Pharmacology, University of Insubria, Varese, Italy
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23
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24
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Abstract
γδT cells function in the regulation of T-cell activation in cancer and have been identified as a novel target for cancer immunotherapy. Activated γδT cells release a series of cytotoxic molecules-including granulysin, perforin, Fas/Fas ligand (Fas-L), and granzymes A and B-to kill target cells. Our previous research has shown that high mobility group nucleosomal-binding domain 2 (HMGN2), which is expressed at a high level in activated CD8T cells, is an antitumor effector molecule of CD8T cells. In the present study, we examined the expression and antitumor effects of HMGN2 in γδT cells. Peripheral blood mononuclear cells (PBMCs) were isolated from healthy donors with a PBMC separation column. PMBCs were stimulated with isopentenyl pyrophosphate (IPP) and interleukin-2 (IL-2) for 10 days for activation and expansion. Activated γδT cells were isolated from IPP-pretreated PBMCs with a Moflo XDP flow cytometry sorter. The expression of HMGN2 in γδT cells was detected by flow cytometry and enzyme-linked immunosorbent assay. The cytotoxic effects of γδT cells and HMGN2 were analyzed by carboxyfluorescein succinimidyl ester labeling. IPP combined with IL-2 induced significant activation and expansion of γδT cells in vitro. HMGN2 was constitutively expressed in γδT cells. IPP-activated γδT cells expressed a high level of HMGN2 that could be detected intracellularly and in the supernatant. Moreover, supernatants of purified γδT cells were sufficient to kill tumor cells and could be blocked with anti-human HMGN2 antibody. This study suggests that HMGN2 is an antitumor effector molecule of γδT cells.
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25
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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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26
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Wu D, Yan WM, Wang HW, Huang D, Luo XP, Ning Q. γδ T Cells Contribute to the Outcome of Murine Fulminant Viral Hepatitis via Effector Cytokines TNF-α and IFN-γ. Curr Med Sci 2018; 38:648-655. [DOI: 10.1007/s11596-018-1926-x] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2017] [Revised: 06/25/2018] [Indexed: 12/25/2022]
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27
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Peters C, Kabelitz D, Wesch D. Regulatory functions of γδ T cells. Cell Mol Life Sci 2018; 75:2125-2135. [PMID: 29520421 PMCID: PMC11105251 DOI: 10.1007/s00018-018-2788-x] [Citation(s) in RCA: 56] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2017] [Revised: 02/07/2018] [Accepted: 02/26/2018] [Indexed: 02/06/2023]
Abstract
γδ T cells share characteristics of innate and adaptive immune cells and are involved in a broad spectrum of pro-inflammatory functions. Nonetheless, there is accumulating evidence that γδ T cells also exhibit regulatory functions. In this review, we describe the different phenotypes of regulatory γδ T cells in correlation with the identified mechanisms of suppression.
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MESH Headings
- Animals
- Genes, cdc/physiology
- Humans
- Immune System Phenomena/physiology
- Immune Tolerance
- Receptors, Antigen, T-Cell, gamma-delta/metabolism
- Receptors, Antigen, T-Cell, gamma-delta/physiology
- T-Lymphocytes, Regulatory/immunology
- T-Lymphocytes, Regulatory/metabolism
- T-Lymphocytes, Regulatory/physiology
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Affiliation(s)
- Christian Peters
- Institute of Immunology, Christian-Albrechts University of Kiel, Arnold-Heller Strasse 3, Haus 17, 24105, Kiel, Germany
| | - Dieter Kabelitz
- Institute of Immunology, Christian-Albrechts University of Kiel, Arnold-Heller Strasse 3, Haus 17, 24105, Kiel, Germany
| | - Daniela Wesch
- Institute of Immunology, Christian-Albrechts University of Kiel, Arnold-Heller Strasse 3, Haus 17, 24105, Kiel, Germany.
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Pranzatelli MR, Allison TJ, McGee NR, Tate ED. Cerebrospinal fluid γδ T cell frequency is age-related: a case-control study of 435 children with inflammatory and non-inflammatory neurological disorders. Clin Exp Immunol 2018; 193:103-112. [PMID: 29485697 DOI: 10.1111/cei.13122] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/26/2018] [Indexed: 11/29/2022] Open
Abstract
Studies of cerebrospinal fluid (CSF) γδ T cells in children are limited, due especially to the lack of control data. In adults, gamma/delta T cells (TCR-γδ) residing in the intrathecal space are sometimes involved in neuroinflammation. To evaluate the possible role of γδ T cells in paediatric neuroinflammation, we immunophenotyped cerebrospinal fluid (CSF) and blood lymphocytes using flow cytometry in a case-control study of 100 children with non-inflammatory neurological disorders (NIND), 312 with opsoclonus-myoclonus (OMS) and 23 with other inflammatory neurological disorders (OIND). In NIND, the negative correlation between CSF γδ T cell frequency and patient age was striking: median frequency of 27% in infants and 3·3% in teens. Interindividual variations were largest in the youngest. There was no gender effect. In all OMS, after correcting for age, only a small effect of OMS severity remained. Measurement of markers for γδ T cell activation [human leucocyte antigen D-related (HLA-DR)], maturation (CD45RA, CD45RO) or intracellular cytokine staining [interleukin (IL)-4, interferon (IFN)-γ] failed to discriminate OMS and NIND groups. Of seven OMS immunotherapies/combinations, none altered the frequency of total CSF γδ T cells or subsets significantly. In OIND, the CSF γδ T cell frequency was < 10% for single samples of other paraneoplastic disorders [anti-neuronal nuclear antibody (ANNA)-1, PCA-1, teratoma-associated syndrome], cerebellar ataxia (post-infectious, ataxia-telangiectasia), acute disseminated encephalomyelitis, neuroborreliosis and encephalitis. This study provides new insights into CSF γδ T cells in the paediatric population. Although their role in CSF remains elusive, the negative age correlation, resistance to immunotherapy and our age cut-off references for NIND are important findings for the design of future paediatric studies.
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Affiliation(s)
- M R Pranzatelli
- National Pediatric Myoclonus Center, Orlando, FL, USA.,National Pediatric Neuroinflammation Organization, Inc., Orlando, FL, USA
| | - T J Allison
- National Pediatric Myoclonus Center, Orlando, FL, USA
| | - N R McGee
- National Pediatric Myoclonus Center, Orlando, FL, USA
| | - E D Tate
- National Pediatric Myoclonus Center, Orlando, FL, USA.,National Pediatric Neuroinflammation Organization, Inc., Orlando, FL, USA
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29
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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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30
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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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31
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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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Promise, Progress, and Pitfalls in the Search for Central Nervous System Biomarkers in Neuroimmunological Diseases: A Role for Cerebrospinal Fluid Immunophenotyping. Semin Pediatr Neurol 2017; 24:229-239. [PMID: 29103430 PMCID: PMC5697729 DOI: 10.1016/j.spen.2017.08.001] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/21/2023]
Abstract
Biomarkers are central to the translational medicine strategic focus, though strict criteria need to be applied to their designation and utility. They are one of the most promising areas of medical research, but the "biomarker life-cycle" must be understood to avoid false-positive and false-negative results. Molecular biomarkers will revolutionize the treatment of neurological diseases, but the rate of progress depends on a bold, visionary stance by neurologists, as well as scientists, biotech and pharmaceutical industries, funding agencies, and regulators. One important tool in studying cell-specific biomarkers is multiparameter flow cytometry. Cerebrospinal fluid immunophenotyping, or immune phenotypic subsets, captures the biology of intrathecal inflammatory processes, and has the potential to guide personalized immunotherapeutic selection and monitor treatment efficacy. Though data exist for some disorders, they are surprisingly lacking in many others, identifying a serious deficit to be overcome. Flow cytometric immunophenotyping provides a valuable, available, and feasible "window" into both adaptive and innate components of neuroinflammation that is currently underutilized.
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33
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The immunologic considerations in human head transplantation. Int J Surg 2017; 41:196-202. [PMID: 28130190 DOI: 10.1016/j.ijsu.2017.01.084] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2016] [Revised: 01/19/2017] [Accepted: 01/20/2017] [Indexed: 11/24/2022]
Abstract
The idea of head transplantation appears at first as unrealistic, unethical, and futile. Here we discuss immunological considerations in human head transplantation. In a separate accompanying article we discuss surgical, ethical, and psychosocial issues concerned in body-to-head transplantation (BHT) [1]. The success of such an unusual allograft, where the donor and the recipient can reject each other, depends on prevention of complex immunologic reactions, especially rejection of the head by the body (graft-vs-host) or probably less likely, the possibility of the head rejecting the total body allograft (host-vs-graft). The technical and immunologic difficulties are enormous, especially since rapid nerve and cord connections and regeneration have not yet been possible to achieve. In this article we begin by briefly reviewing neuro-immunologic issues that may favor BHT such as the blood brain barrier (BBB) and point out its shortcomings. And we touch on the cellular and humoral elements in the brain proper that differ in some respects from those in other organs and in the periphery. Based on recent successes in vascular composite allografts (VCAs), we will elaborate on potential specific advantages and difficulties in BHT of various available immunosuppressive medications already utilized in VCAs. The risk/benefit ratio of these drugs will be emphasized in relation to direct brain toxicity such as seizure disorders, interference, or promotion of nerve regeneration, and potentiation of cerebral viral infections. The final portion of this article will focus on pre-transplant immunologic manipulation of the deceased donor body along with pretreatment of the recipient.
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34
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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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36
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Chen H, You H, Wang L, Zhang X, Zhang J, He W. Chaperonin-containing T-complex Protein 1 Subunit ζ Serves as an Autoantigen Recognized by Human Vδ2 γδ T Cells in Autoimmune Diseases. J Biol Chem 2016; 291:19985-93. [PMID: 27489109 DOI: 10.1074/jbc.m115.700070] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2015] [Indexed: 01/20/2023] Open
Abstract
Human γδ T cells recognize conserved endogenous and stress-induced antigens typically associated with autoimmune diseases. However, the role of γδ T cells in autoimmune diseases is not clear. Few autoimmune disease-related antigens recognized by T cell receptor (TCR) γδ have been defined. In this study, we compared Vδ2 TCR complementarity-determining region 3 (CDR3) between systemic lupus erythematosus (SLE) patients and healthy donors. Results show that CDR3 length distribution differed significantly and displayed oligoclonal characteristics in SLE patients when compared with healthy donors. We found no difference in the frequency of Jδ gene fragment usage between these two groups. According to the dominant CDR3δ sequences in SLE patients, synthesized SL2 peptides specifically bound to human renal proximal tubular epithelial cell line HK-2; SL2-Vm, a mutant V sequence of SL2, did not bind. We identified the putative protein ligand chaperonin-containing T-complex protein 1 subunit ζ (CCT6A) using SL2 as a probe in HK-2 cell protein extracts by affinity chromatography and liquid chromatography-electrospray ionization-tandem mass spectrometry analysis. We found CCT6A expression on the surface of HK-2 cells. Cytotoxicity of only Vδ2 γδ T cells to HK-2 cells was blocked by anti-CCT6A antibody. Finally, we note that CCT6A concentration was significantly increased in plasma of SLE and rheumatoid arthritis patients. These data suggest that CCT6A is a novel autoantigen recognized by Vδ2 γδ T cells, which deepens our understanding of mechanisms in autoimmune diseases.
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Affiliation(s)
- Hui Chen
- From the Department of Immunology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and School of Basic Medicine, Peking Union Medical College, State Key Laboratory of Medical Molecular Biology, Beijing 100005, China and
| | - Hongqin You
- From the Department of Immunology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and School of Basic Medicine, Peking Union Medical College, State Key Laboratory of Medical Molecular Biology, Beijing 100005, China and
| | - Lifang Wang
- From the Department of Immunology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and School of Basic Medicine, Peking Union Medical College, State Key Laboratory of Medical Molecular Biology, Beijing 100005, China and
| | - Xuan Zhang
- the Department of Rheumatology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing 100730, China
| | - Jianmin Zhang
- From the Department of Immunology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and School of Basic Medicine, Peking Union Medical College, State Key Laboratory of Medical Molecular Biology, Beijing 100005, China and
| | - Wei He
- From the Department of Immunology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and School of Basic Medicine, Peking Union Medical College, State Key Laboratory of Medical Molecular Biology, Beijing 100005, China and
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37
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Kavrochorianou N, Markogiannaki M, Haralambous S. IFN-β differentially regulates the function of T cell subsets in MS and EAE. Cytokine Growth Factor Rev 2016; 30:47-54. [DOI: 10.1016/j.cytogfr.2016.03.013] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/29/2016] [Accepted: 03/21/2016] [Indexed: 12/30/2022]
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38
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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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39
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Ujiie H, Shevach EM. γδ T Cells Protect the Liver and Lungs of Mice from Autoimmunity Induced by Scurfy Lymphocytes. THE JOURNAL OF IMMUNOLOGY 2016; 196:1517-28. [PMID: 26773142 DOI: 10.4049/jimmunol.1501774] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/05/2015] [Accepted: 12/10/2015] [Indexed: 02/06/2023]
Abstract
γδ T cells have been shown to have immunoregulatory functions in several experimental autoimmune models. A mutation of the Foxp3 gene leads to the absence of regulatory T cells (Tregs) and a fatal systemic autoimmune disease in scurfy mice. Transfer of scurfy lymphocytes to RAG deficient (RAG(-/-)) recipients reproduces the inflammatory phenotype of the scurfy donor, including hepatitis and pneumonitis. In this study, we show that TCRα(-/-) recipients, which lack αβ T cells but have γδ T cells and B cells, are significantly protected from the hepatitis and pneumonitis, but not the dermatitis, induced by adoptive transfer of scurfy lymphocytes. Cotransfer of γδ T cells, but not B cells, prevented hepatitis and pneumonitis in RAG(-/-) recipients of scurfy lymphocytes. γδ T cells in the TCRα(-/-) recipients of scurfy cells markedly expanded and expressed a highly activated (CD62L(lo)CD44(hi)) phenotype. The activated γδ T cells expressed high levels of CD39 and NKG2D on their cell surface. A high frequency of scurfy T cells in TCRα(-/-) recipients produced IL-10, suggesting that γδ T cells may enhance suppressor cytokine production from scurfy T cells in TCRα(-/-) recipients. This study indicates that γδ T cells may contribute to the maintenance of immunological homeostasis by suppressing autoreactive T cells in liver and lung.
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Affiliation(s)
- Hideyuki Ujiie
- Laboratory of Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892
| | - Ethan M Shevach
- Laboratory of Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892
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40
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Rezende RM, da Cunha AP, Kuhn C, Rubino S, M'Hamdi H, Gabriely G, Vandeventer T, Liu S, Cialic R, Pinheiro-Rosa N, Oliveira RP, Gaublomme JT, Obholzer N, Kozubek J, Pochet N, Faria AMC, Weiner HL. Identification and characterization of latency-associated peptide-expressing γδ T cells. Nat Commun 2015; 6:8726. [PMID: 26644347 PMCID: PMC4686827 DOI: 10.1038/ncomms9726] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2015] [Accepted: 09/24/2015] [Indexed: 02/06/2023] Open
Abstract
γδ T cells are a subset of lymphocytes specialized in protecting the host against pathogens and tumours. Here we describe a subset of regulatory γδ T cells that express the latency-associated peptide (LAP), a membrane-bound TGF-β1. Thymic CD27+IFN-γ+CCR9+α4β7+TCRγδ+ cells migrate to the periphery, particularly to Peyer's patches and small intestine lamina propria, where they upregulate LAP, downregulate IFN-γ via ATF-3 expression and acquire a regulatory phenotype. TCRγδ+LAP+ cells express antigen presentation molecules and function as antigen presenting cells that induce CD4+Foxp3+ regulatory T cells, although TCRγδ+LAP+ cells do not themselves express Foxp3. Identification of TCRγδ+LAP+ regulatory cells provides an avenue for understanding immune regulation and biologic processes linked to intestinal function and disease. Latency-associated peptide (LAP) is a membrane-bound form of TGF-β1. Here the authors show that LAP marks a subset of regulatory γδ T cells with innate gut-homing properties, which present antigen and induce CD4+ Foxp3+ in Peyer's patches and lamina propria.
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Affiliation(s)
- Rafael M Rezende
- Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA
| | - Andre P da Cunha
- Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA
| | - Chantal Kuhn
- Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA
| | - Stephen Rubino
- Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA
| | - Hanane M'Hamdi
- Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA.,Rheumatology Unit, Department of Medicine at Karolinska University Hospital, Karolinska Institute, Solna, Stockholm 17177, Sweden
| | - Galina Gabriely
- Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA
| | - Tyler Vandeventer
- Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA
| | - Shirong Liu
- Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA
| | - Ron Cialic
- Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA
| | - Natalia Pinheiro-Rosa
- Department of Biochemistry and Immunology, Institute of Biological Sciences, Federal University of Minas Gerais, Belo Horizonte 31.270-901, Brazil
| | - Rafael P Oliveira
- Department of Biochemistry and Immunology, Institute of Biological Sciences, Federal University of Minas Gerais, Belo Horizonte 31.270-901, Brazil
| | - Jellert T Gaublomme
- Department of Chemistry and Chemical Biology, Harvard University, Cambridge, Massachusetts 02138, USA.,Department of Physics, Harvard University, Cambridge, Massachusetts 02138, USA
| | - Nikolaus Obholzer
- Program in Translational NeuroPsychiatric Genomics, Institute for the Neurosciences, Departments of Neurology and Psychiatry, Brigham and Women's Hospital, Boston, Massachusetts 02115, USA
| | - James Kozubek
- Program in Translational NeuroPsychiatric Genomics, Institute for the Neurosciences, Departments of Neurology and Psychiatry, Brigham and Women's Hospital, Boston, Massachusetts 02115, USA
| | - Nathalie Pochet
- Program in Translational NeuroPsychiatric Genomics, Institute for the Neurosciences, Departments of Neurology and Psychiatry, Brigham and Women's Hospital, Boston, Massachusetts 02115, USA.,Broad Institute of Massachusetts Institute of Technology (MIT) and Harvard, Cambridge, Massachusetts 02142, USA
| | - Ana M C Faria
- Department of Biochemistry and Immunology, Institute of Biological Sciences, Federal University of Minas Gerais, Belo Horizonte 31.270-901, Brazil
| | - Howard L Weiner
- Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA
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41
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Sonar S, Lal G. Role of Tumor Necrosis Factor Superfamily in Neuroinflammation and Autoimmunity. Front Immunol 2015; 6:364. [PMID: 26257732 PMCID: PMC4507150 DOI: 10.3389/fimmu.2015.00364] [Citation(s) in RCA: 76] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2015] [Accepted: 07/05/2015] [Indexed: 12/18/2022] Open
Abstract
Tumor necrosis factor superfamily (TNFSF) molecules play an important role in the activation, proliferation, differentiation, and migration of immune cells into the central nervous system (CNS). Several TNF superfamily molecules are known to control alloimmunity, autoimmunity, and immunity. Development of transgenic and gene knockout animals, and monoclonal antibodies against TNFSF molecules have increased our understanding of individual receptor-ligand interactions, and their intracellular signaling during homeostasis and neuroinflammation. A strong clinical association has been observed between TNFSF members and CNS autoimmunity such as multiple sclerosis and also in its animal model experimental autoimmune encephalomyelitis. Therefore, they are promising targets for alternative therapeutic options to control autoimmunity. Although, TNFSF ligands are widely distributed and have diverse functions, we have restricted the discussions in this review to TNFSF receptor-ligand interactions and their role in the pathogenesis of neuroinflammation and CNS autoimmunity.
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42
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γδ T Cells Are Required for M2 Macrophage Polarization and Resolution of Ozone-Induced Pulmonary Inflammation in Mice. PLoS One 2015; 10:e0131236. [PMID: 26135595 PMCID: PMC4489797 DOI: 10.1371/journal.pone.0131236] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2015] [Accepted: 05/29/2015] [Indexed: 12/21/2022] Open
Abstract
We examined the role of γδ T cells in the induction of alternatively activated M2 macrophages and the resolution of inflammation after ozone exposure. Wildtype (WT) mice and mice deficient in γδ T cells (TCRδ-/- mice) were exposed to air or to ozone (0.3 ppm for up to 72h) and euthanized immediately or 1, 3, or 5 days after cessation of exposure. In WT mice, M2 macrophages accumulated in the lungs over the course of ozone exposure. Pulmonary mRNA abundance of the M2 genes, Arg1, Retnla, and Clec10a, also increased after ozone. In contrast, no evidence of M2 polarization was observed in TCRδ-/- mice. WT but not TCRδ-/- mice expressed the M2c polarizing cytokine, IL-17A, after ozone exposure and WT mice treated with an IL-17A neutralizing antibody exhibited attenuated ozone-induced M2 gene expression. In WT mice, ozone-induced increases in bronchoalveolar lavage neutrophils and macrophages resolved quickly after cessation of ozone exposure returning to air exposed levels within 3 days. However, lack of M2 macrophages in TCRδ-/- mice was associated with delayed clearance of inflammatory cells after cessation of ozone and increased accumulation of apoptotic macrophages in the lungs. Delayed restoration of normal lung architecture was also observed in TCRδ-/- mice. In summary, our data indicate that γδ T cells are required for the resolution of ozone-induced inflammation, likely because γδ T cells, through their secretion of IL-17A, contribute to changes in macrophage polarization that promote clearance of apoptotic cells.
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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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Deretzi G, Kountouras J, Polyzos SA, Koutlas E, Pelidou SH, Xeromerisiou G, Zavos C, Tsiptsios I. Polyautoimmunity in a Greek cohort of multiple sclerosis. Acta Neurol Scand 2015; 131:225-30. [PMID: 25270060 DOI: 10.1111/ane.12308] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/22/2014] [Indexed: 01/01/2023]
Abstract
OBJECTIVES The aim of this study was to assess the existence of polyautoimmunity in a Greek cohort of multiple sclerosis (MS), particularly multiple autoimmune syndrome (MAS), i.e., the presence of three or more distinct autoimmune disorders (ADs) in the same individual. METHODS Cross-sectional control study. RESULTS The overall prevalence of polyautoimmunity in 2140 MS patients (female to male ratio: 2.1:1) was 8.3% (vs 6.07% in 1580 matched control participants, P = 0.008) mainly due to differences in autoimmune thyroid disorders (AITD) and vitiligo. The prevalence of MAS was 1.0%. The most frequent diseases encountered in MS were organ-specific ADs. There was no statistical difference in the total rates of ADs between female and male MS patients. There were higher rates of AITD in women (P = 0.004) and higher rates of iritis (P = 0.039) and ankylosing spondylitis (P = 0.003) in men. MS was diagnosed in the same year with AD in 7.4% of patients with additional ADs, earlier than AD in 42.0% and later than AD in 50.6%. CONCLUSION Polyautoimmunity and particularly MAS occur more frequently in MS patients than in control participants indicating that MS may be part of a generalized susceptibility to autoimmunity. Therefore, polyautoimmunity may be implicated in the etiopathogenesis of MS-related ADs, with a potential impact on relative therapeutic strategies.
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Affiliation(s)
- G. Deretzi
- Department of Neurology; Multiple Sclerosis Unit; Papageorgiou General Hospital; Thessaloniki Greece
| | - J. Kountouras
- Department of Gastroenterology; Second Medical Clinic; Aristotle University of Thessaloniki; Ippokration Hospital; Thessaloniki Greece
| | - S. A. Polyzos
- Department of Gastroenterology; Second Medical Clinic; Aristotle University of Thessaloniki; Ippokration Hospital; Thessaloniki Greece
| | - E. Koutlas
- Department of Neurology; Multiple Sclerosis Unit; Papageorgiou General Hospital; Thessaloniki Greece
| | - S.-H. Pelidou
- Department of Neurology; Ioannina University; Ioannina Greece
| | - G. Xeromerisiou
- Department of Neurology; Multiple Sclerosis Unit; Papageorgiou General Hospital; Thessaloniki Greece
| | - C. Zavos
- Department of Gastroenterology; Second Medical Clinic; Aristotle University of Thessaloniki; Ippokration Hospital; Thessaloniki Greece
| | - I. Tsiptsios
- Department of Neurology; Multiple Sclerosis Unit; Papageorgiou General Hospital; Thessaloniki Greece
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Mastorodemos V, Ioannou M, Verginis P. Cell-based modulation of autoimmune responses in multiple sclerosis and experimental autoimmmune encephalomyelitis: therapeutic implications. Neuroimmunomodulation 2015; 22:181-95. [PMID: 24852748 DOI: 10.1159/000362370] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/21/2013] [Accepted: 03/20/2014] [Indexed: 11/19/2022] Open
Abstract
Multiple sclerosis (MS) is a prototypic autoimmune inflammatory disorder of the central nervous system (CNS). MS pathogenesis is a complex phenomenon that is influenced by genetic and environmental factors that lead to the dysregulation of immune homeostasis and tolerance. It has been shown that pathogenic T lymphocyte subsets, such as T helper 1 (Th1) and Th17 cells, play a crucial role in the autoimmune cascade influencing disease initiation, progression and subsequent tissue damage during MS. On the other hand, several mechanisms have been described in both patients and animal models of MS with the potential to modulate myelin-specific autoimmune responses and to facilitate amelioration of disease pathology. To this end, regulatory T cells (Tregs) are considered to be a powerful cell subset not only in the maintenance of homeostasis but also in the re-establishment of tolerance. Along these lines, other cell subsets such as dendritic cells (DCs), myeloid-derived suppressor cells (MDSCs), γδ T cells and natural killer (NK) cells have been shown to regulate the autoimmune response in the CNS under certain circumstances. This review will attempt to summarize the relevant knowledge of the regulatory mechanisms exerted by immune cells in MS that could hold the promise for the design of novel therapeutic strategies.
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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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Hussain RZ, Hayardeny L, Cravens PC, Yarovinsky F, Eagar TN, Arellano B, Deason K, Castro-Rojas C, Stüve O. Immune surveillance of the central nervous system in multiple sclerosis--relevance for therapy and experimental models. J Neuroimmunol 2014; 276:9-17. [PMID: 25282087 PMCID: PMC4301841 DOI: 10.1016/j.jneuroim.2014.08.622] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2014] [Revised: 08/15/2014] [Accepted: 08/20/2014] [Indexed: 12/25/2022]
Abstract
Treatment of central nervous system (CNS) autoimmune disorders frequently involves the reduction, or depletion of immune-competent cells. Alternatively, immune cells are being sequestered away from the target organ by interfering with their movement from secondary lymphoid organs, or their migration into tissues. These therapeutic strategies have been successful in multiple sclerosis (MS), the most prevalent autoimmune inflammatory disorder of the CNS. However, many of the agents that are currently approved or in clinical development also have severe potential adverse effects that stem from the very mechanisms that mediate their beneficial effects by interfering with CNS immune surveillance. This review will outline the main cellular components of the innate and adaptive immune system that participate in host defense and maintain immune surveillance of the CNS. Their pathogenic role in MS and its animal model experimental autoimmune encephalomyelitis (EAE) is also discussed. Furthermore, an experimental model is introduced that may assist in evaluating the effect of therapeutic interventions on leukocyte homeostasis and function within the CNS. This model or similar models may become a useful tool in the repertoire of pre-clinical tests of pharmacological agents to better explore their potential for adverse events.
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Affiliation(s)
- Rehana Z Hussain
- Department of Neurology and Neurotherapeutics, University of Texas Southwestern Medical Center at Dallas, TX, USA
| | | | - Petra C Cravens
- Department of Neurology and Neurotherapeutics, University of Texas Southwestern Medical Center at Dallas, TX, USA
| | - Felix Yarovinsky
- Department of Immunology, University of Texas Southwestern Medical Center at Dallas, TX, USA
| | - Todd N Eagar
- Histocompatibility and Transplant Immunology, Department of Pathology and Genomic Medicine, The Methodist Hospital Physician Organization, Houston, TX, USA
| | - Benjamine Arellano
- Department of Neurology and Neurotherapeutics, University of Texas Southwestern Medical Center at Dallas, TX, USA
| | - Krystin Deason
- Department of Neurology and Neurotherapeutics, University of Texas Southwestern Medical Center at Dallas, TX, USA
| | - Cyd Castro-Rojas
- Department of Neurology and Neurotherapeutics, University of Texas Southwestern Medical Center at Dallas, TX, USA
| | - Olaf Stüve
- Department of Neurology and Neurotherapeutics, University of Texas Southwestern Medical Center at Dallas, TX, USA; Neurology Section, VA North Texas Health Care System, Medical Service, Dallas, TX, USA; Department of Neurology, Klinikum rechts der Isar, Technische Universität München, Germany.
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Blink SE, Caldis MW, Goings GE, Harp CT, Malissen B, Prinz I, Xu D, Miller SD. γδ T cell subsets play opposing roles in regulating experimental autoimmune encephalomyelitis. Cell Immunol 2014; 290:39-51. [PMID: 24860937 DOI: 10.1016/j.cellimm.2014.04.013] [Citation(s) in RCA: 57] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2014] [Revised: 04/21/2014] [Accepted: 04/28/2014] [Indexed: 12/29/2022]
Abstract
γδ T cells are resident in cerebrospinal fluid and central nervous system (CNS) lesions of multiple sclerosis (MS) patients, but as multifaceted cells exhibiting innate and adaptive characteristics, their function remains unknown. Previous studies in experimental autoimmune encephalomyelitis (EAE) are contradictory and identified these cells as either promoting or suppressing disease pathogenesis. This study examines distinct γδ T cell subsets during EAE and indicates they mediate differential functions in CNS inflammation and demyelination resulting in pathogenesis or protection. We identified two γδ subsets in the CNS, Vγ1(+) and Vγ4(+), with distinct cytokine profiles and tissue specificity. Anti-γδ T cell receptor (TCR) monoclonal antibody (mAb) administration results in activation and downregulation of surface TCR, rendering the cells undetectable, but with opposing effects: anti-Vγ4 treatment exacerbates disease whereas anti-Vγ1 treatment is protective. The Vγ4(+) subset produces multiple pro-inflammatory cytokines including high levels of IL-17, and accounts for 15-20% of the interleukin-17 (IL-17) producing cells in the CNS, but utilize a variant transcriptional program than CD4(+) Th17 cells. In contrast, the Vγ1 subset produces CCR5 ligands, which may promote regulatory T cell differentiation. γδ T cell subsets thus play distinct and opposing roles during EAE, providing an explanation for previous reports and suggesting selective targeting to optimize regulation as a potential therapy for MS.
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Affiliation(s)
- Sarah E Blink
- Department of Microbiology-Immunology and Interdepartmental Immunobiology Center, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, United States
| | - Matthew W Caldis
- Department of Microbiology-Immunology and Interdepartmental Immunobiology Center, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, United States
| | - Gwendolyn E Goings
- Department of Microbiology-Immunology and Interdepartmental Immunobiology Center, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, United States
| | - Christopher T Harp
- Department of Microbiology-Immunology and Interdepartmental Immunobiology Center, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, United States
| | - Bernard Malissen
- Centre d'Immunologie de Marseille-Luminy, Université de la Méditerranée, Case 906, Institut National de la Santé et de la Recherche Médicale, U631, Centre National de la Recherche Scientifique, UMR6102, 13288 Marseille, France
| | - Immo Prinz
- Hannover Medical School, Institute for Immunology, 30625 Hannover, Germany
| | - Dan Xu
- Department of Microbiology-Immunology and Interdepartmental Immunobiology Center, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, United States
| | - Stephen D Miller
- Department of Microbiology-Immunology and Interdepartmental Immunobiology Center, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, United States.
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Fillatreau S, Anderton SM. B-cell function in CNS inflammatory demyelinating disease: a complexity of roles and a wealth of possibilities. Expert Rev Clin Immunol 2014; 3:565-78. [DOI: 10.1586/1744666x.3.4.565] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
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Wu YL, Ding YP, Tanaka Y, Shen LW, Wei CH, Minato N, Zhang W. γδ T cells and their potential for immunotherapy. Int J Biol Sci 2014; 10:119-35. [PMID: 24520210 PMCID: PMC3920167 DOI: 10.7150/ijbs.7823] [Citation(s) in RCA: 105] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2013] [Accepted: 12/17/2013] [Indexed: 12/19/2022] Open
Abstract
Vγ9Vδ2 (also termed Vγ2Vδ2) T cells, a major human peripheral blood γδ T cell subset, recognize microbial (E)-4-hydroxy-3-methylbut-2-enyl diphosphate and endogenous isopentenyl diphosphate in a TCR-dependent manner. The recognition does not require specific accessory cells, antigen uptake, antigen processing, or MHC class I, class II, or class Ib expression. This subset of T cells plays important roles in mediating innate immunity against a wide variety of infections and displays potent and broad cytotoxic activity against human tumor cells. Because γδT cells express both natural killer receptors such as NKG2D and γδ T cell receptors, they are considered to represent a link between innate and adaptive immunity. In addition, activated γδ T cells express a high level of antigen-presenting cell-related molecules and can present peptide antigens derived from destructed cells to αβ T cells. Utilizing these antimicrobial and anti-tumor properties of γδ T cells, preclinical and clinical trials have been conducted to develop novel immunotherapies for infections and malignancies. Here, we review the immunological properties of γδ T cells including the underlying recognition mechanism of nonpeptitde antigens and summarize the results of γδ T cell-based therapies so far performed. Based on the results of the reported trials, γδ T cells appear to be a promising tool for novel immunotherapies against certain types of diseases.
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Affiliation(s)
- Yan-Ling Wu
- 1. Lab of Molecular Immunology, Zhejiang Provincial Center for Disease Control and Prevention, 630 Xincheng Road, Hangzhou, 310051, China
| | - Yan-Ping Ding
- 1. Lab of Molecular Immunology, Zhejiang Provincial Center for Disease Control and Prevention, 630 Xincheng Road, Hangzhou, 310051, China
- 2. Lab of Chemical Biology and Molecular Drug Design, College of Pharmaceutical Science, Zhejiang University of Technology, 18 Chaowang Road, Hangzhou, 310014, China
| | - Yoshimasa Tanaka
- 3. Center for Innovation in Immunoregulative Technology and Therapeutics, Graduate School of Medicine, Kyoto University, Kyoto, 606-8501, Japan
| | - Li-Wen Shen
- 2. Lab of Chemical Biology and Molecular Drug Design, College of Pharmaceutical Science, Zhejiang University of Technology, 18 Chaowang Road, Hangzhou, 310014, China
| | - Chuan-He Wei
- 2. Lab of Chemical Biology and Molecular Drug Design, College of Pharmaceutical Science, Zhejiang University of Technology, 18 Chaowang Road, Hangzhou, 310014, China
| | - Nagahiro Minato
- 4. Department of Immunology and Cell Biology, Graduate School of Medicine, Kyoto University, Kyoto, 606-8501, Japan
| | - Wen Zhang
- 2. Lab of Chemical Biology and Molecular Drug Design, College of Pharmaceutical Science, Zhejiang University of Technology, 18 Chaowang Road, Hangzhou, 310014, China
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