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Zhang W, Kong D, Zhang X, Hu L, Nian Y, Shen Z. T cell aging and exhaustion: Mechanisms and clinical implications. Clin Immunol 2025; 275:110486. [PMID: 40120658 DOI: 10.1016/j.clim.2025.110486] [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: 01/25/2025] [Revised: 03/11/2025] [Accepted: 03/19/2025] [Indexed: 03/25/2025]
Abstract
T cell senescence and exhaustion represent critical aspects of adaptive immune system dysfunction, with profound implications for health and the development of disease prevention and therapeutic strategies. These processes, though distinct, are interconnected at the molecular level, leading to impaired effector functions and reduced proliferative capacity of T cells. Such impairments increase susceptibility to diseases and diminish the efficacy of vaccines and treatments. Importantly, T cell senescence and exhaustion can dynamically influence each other, particularly in the context of chronic diseases. A deeper understanding of the molecular mechanisms underlying T cell senescence and exhaustion, as well as their interplay, is essential for elucidating the pathogenesis of related diseases and restoring dysfunctional immune responses. This knowledge will pave the way for the development of targeted therapeutic interventions and strategies to enhance immune competence. This review aims to summarize the characteristics, mechanisms, and disease associations of T cell senescence and exhaustion, while also delineating the distinctions and intersections between these two states to enhance our comprehension.
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Affiliation(s)
- Weiqi Zhang
- School of Medicine, Nankai University, Tianjin, China; Research Institute of Transplant Medicine, Nankai University, Tianjin, China; Tianjin Key Laboratory for Organ Transplantation, Tianjin, China.
| | - Dejun Kong
- School of Medicine, Nankai University, Tianjin, China; Research Institute of Transplant Medicine, Nankai University, Tianjin, China; Tianjin Key Laboratory for Organ Transplantation, Tianjin, China.
| | - Xiaohan Zhang
- School of Medicine, Nankai University, Tianjin, China; Research Institute of Transplant Medicine, Nankai University, Tianjin, China; Tianjin Key Laboratory for Organ Transplantation, Tianjin, China.
| | - Lu Hu
- Tianjin Medical University First Central Clinical College, Tianjin, China.
| | - Yeqi Nian
- School of Medicine, Nankai University, Tianjin, China; Research Institute of Transplant Medicine, Nankai University, Tianjin, China; Tianjin Key Laboratory for Organ Transplantation, Tianjin, China; Key Laboratory of Transplant Medicine, Chinese Academy of Medical Science, Tianjin, China; Department of Kidney Transplant, Tianjin First Central Hospital, Tianjin, China.
| | - Zhongyang Shen
- School of Medicine, Nankai University, Tianjin, China; Research Institute of Transplant Medicine, Nankai University, Tianjin, China; Tianjin Key Laboratory for Organ Transplantation, Tianjin, China; Key Laboratory of Transplant Medicine, Chinese Academy of Medical Science, Tianjin, China.
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Fan Q, Wang Y, Cheng J, Pan B, Zang X, Liu R, Deng Y. Single-cell RNA-seq reveals T cell exhaustion and immune response landscape in osteosarcoma. Front Immunol 2024; 15:1362970. [PMID: 38629071 PMCID: PMC11018946 DOI: 10.3389/fimmu.2024.1362970] [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: 12/29/2023] [Accepted: 03/18/2024] [Indexed: 04/19/2024] Open
Abstract
Background T cell exhaustion in the tumor microenvironment has been demonstrated as a substantial contributor to tumor immunosuppression and progression. However, the correlation between T cell exhaustion and osteosarcoma (OS) remains unclear. Methods In our present study, single-cell RNA-seq data for OS from the GEO database was analysed to identify CD8+ T cells and discern CD8+ T cell subsets objectively. Subgroup differentiation trajectory was then used to pinpoint genes altered in response to T cell exhaustion. Subsequently, six machine learning algorithms were applied to develop a prognostic model linked with T cell exhaustion. This model was subsequently validated in the TARGETs and Meta cohorts. Finally, we examined disparities in immune cell infiltration, immune checkpoints, immune-related pathways, and the efficacy of immunotherapy between high and low TEX score groups. Results The findings unveiled differential exhaustion in CD8+ T cells within the OS microenvironment. Three genes related to T cell exhaustion (RAD23A, SAC3D1, PSIP1) were identified and employed to formulate a T cell exhaustion model. This model exhibited robust predictive capabilities for OS prognosis, with patients in the low TEX score group demonstrating a more favorable prognosis, increased immune cell infiltration, and heightened responsiveness to treatment compared to those in the high TEX score group. Conclusion In summary, our research elucidates the role of T cell exhaustion in the immunotherapy and progression of OS, the prognostic model constructed based on T cell exhaustion-related genes holds promise as a potential method for prognostication in the management and treatment of OS patients.
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Affiliation(s)
- Qizhi Fan
- Department of Spine Surgery, Third Xiangya Hospital, Central South University, Changsha, China
| | - Yiyan Wang
- Department of Spine Surgery, Third Xiangya Hospital, Central South University, Changsha, China
| | - Jun Cheng
- Department of Spine Surgery, Third Xiangya Hospital, Central South University, Changsha, China
| | - Boyu Pan
- Department of Orthopedics, Third Hospital of Changsha, Changsha, China
| | - Xiaofang Zang
- Department of Spine Surgery, Third Xiangya Hospital, Central South University, Changsha, China
| | - Renfeng Liu
- Department of Spine Surgery, Third Xiangya Hospital, Central South University, Changsha, China
| | - Youwen Deng
- Department of Spine Surgery, Third Xiangya Hospital, Central South University, Changsha, China
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Tian W, Qin G, Jia M, Li W, Cai W, Wang H, Zhao Y, Bao X, Wei W, Zhang Y, Shao Q. Hierarchical transcriptional network governing heterogeneous T cell exhaustion and its implications for immune checkpoint blockade. Front Immunol 2023; 14:1198551. [PMID: 37398674 PMCID: PMC10311999 DOI: 10.3389/fimmu.2023.1198551] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2023] [Accepted: 06/06/2023] [Indexed: 07/04/2023] Open
Abstract
The fundamental principle of immune checkpoint blockade (ICB) is to protect tumor-infiltrating T cells from being exhausted. Despite the remarkable success achieved by ICB treatment, only a small group of patients benefit from it. Characterized by a hypofunctional state with the expression of multiple inhibitory receptors, exhausted T (Tex) cells are a major obstacle in improving ICB. T cell exhaustion is a progressive process which adapts to persistent antigen stimulation in chronic infections and cancers. In this review, we elucidate the heterogeneity of Tex cells and offer new insights into the hierarchical transcriptional regulation of T cell exhaustion. Factors and signaling pathways that induce and promote exhaustion are also summarized. Moreover, we review the epigenetic and metabolic alterations of Tex cells and discuss how PD-1 signaling affects the balance between T cell activation and exhaustion, aiming to provide more therapeutic targets for applications of combinational immunotherapies.
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Affiliation(s)
- Weihong Tian
- Department of Immunology, School of Medicine, Jiangsu University, Zhenjiang, Jiangsu, China
- Life Science Institute, Jinzhou Medical University, Jinzhou, Liaoning, China
| | - Gaofeng Qin
- Life Science Institute, Jinzhou Medical University, Jinzhou, Liaoning, China
| | - Miaomiao Jia
- Jiaxing Key Laboratory of Pathogenic Microbiology, Jiaxing Center for Disease Control and Prevention, Jiaxing, Zhejiang, China
| | - Wuhao Li
- Department of Immunology, School of Medicine, Jiangsu University, Zhenjiang, Jiangsu, China
| | - Weili Cai
- Institute of Medical Genetics and Reproductive Immunity, School of Medical Science and Laboratory Medicine, Jiangsu College of Nursing, Huai’an, Jiangsu, China
| | - Hui Wang
- Department of Immunology, School of Medicine, Jiangsu University, Zhenjiang, Jiangsu, China
| | - Yangjing Zhao
- Department of Immunology, School of Medicine, Jiangsu University, Zhenjiang, Jiangsu, China
| | - Xuanwen Bao
- Department of Medical Oncology, The First Affiliated Hospital, School of Medicine, Zhejiang University & Key Laboratory of Cancer Prevention and Intervention, Ministry of Education, Hangzhou, Zhejiang, China
| | - Wangzhi Wei
- Life Science Institute, Jinzhou Medical University, Jinzhou, Liaoning, China
| | - Yu Zhang
- Life Science Institute, Jinzhou Medical University, Jinzhou, Liaoning, China
| | - Qixiang Shao
- Department of Immunology, School of Medicine, Jiangsu University, Zhenjiang, Jiangsu, China
- Institute of Medical Genetics and Reproductive Immunity, School of Medical Science and Laboratory Medicine, Jiangsu College of Nursing, Huai’an, Jiangsu, China
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Fang L, Liu K, Liu C, Wang X, Ma W, Xu W, Wu J, Sun C. Tumor accomplice: T cell exhaustion induced by chronic inflammation. Front Immunol 2022; 13:979116. [PMID: 36119037 PMCID: PMC9479340 DOI: 10.3389/fimmu.2022.979116] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2022] [Accepted: 08/22/2022] [Indexed: 11/17/2022] Open
Abstract
The development and response to treatment of tumor are modulated by inflammation, and chronic inflammation promotes tumor progression and therapy resistance. This article summarizes the dynamic evolution of inflammation from acute to chronic in the process of tumor development, and its effect on T cells from activation to the promotion of exhaustion. We review the mechanisms by which inflammatory cells and inflammatory cytokines regulate T cell exhaustion and methods for targeting chronic inflammation to improve the efficacy of immunotherapy. It is great significance to refer to the specific state of inflammation and T cells at different stages of tumor development for accurate clinical decision-making of immunotherapy and improving the efficiency of tumor immunotherapy.
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Affiliation(s)
- Liguang Fang
- College of First Clinical Medicine, Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Kunjing Liu
- College of First Clinical Medicine, Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Cun Liu
- College of Traditional Chinese Medicine, Weifang Medical University, Weifang, China
| | - Xiaomin Wang
- Department of Inspection, The Medical Faculty of Qingdao University, Qingdao, China
| | - Wenzhe Ma
- State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Macau, Macao SAR, China
| | - Wenhua Xu
- Department of Inspection, The Medical Faculty of Qingdao University, Qingdao, China
| | - Jibiao Wu
- College of Traditional Chinese Medicine, Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Changgang Sun
- College of Traditional Chinese Medicine, Weifang Medical University, Weifang, China
- Department of Oncology, Weifang Traditional Chinese Hospital, Weifang, China
- *Correspondence: Changgang Sun,
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Costa-Madeira JC, Trindade GB, Almeida PHP, Silva JS, Carregaro V. T Lymphocyte Exhaustion During Human and Experimental Visceral Leishmaniasis. Front Immunol 2022; 13:835711. [PMID: 35585983 PMCID: PMC9108272 DOI: 10.3389/fimmu.2022.835711] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2021] [Accepted: 04/07/2022] [Indexed: 11/18/2022] Open
Abstract
A key point of immunity against protozoan Leishmania parasites is the development of an optimal T cell response, which includes a low apoptotic rate, high proliferative activity and polyfunctionality. During acute infection, antigen-specific T cells recognize the pathogen resulting in pathogen control but not elimination, promoting the development and the maintenance of a population of circulating effector cells that mount rapid response quickly after re-exposure to the parasite. However, in the case of visceral disease, the functionality of specific T cells is lost during chronic infection, resulting in inferior effector functions, poor response to specific restimulation, and suboptimal homeostatic proliferation, a term referred to as T cell exhaustion. Multiple factors, including parasite load, infection duration and host immunity, affect T lymphocyte exhaustion. These factors contribute to antigen persistence by promoting inhibitory receptor expression and sustained production of soluble mediators, influencing suppressive cell function and the release of endogenous molecules into chronically inflamed tissue. Together, these signals encourage several changes, reprogramming cells into a quiescent state, which reflects disease progression to more severe forms, and development of acquired resistance to conventional drugs to treat the disease. These points are discussed in this review.
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Affiliation(s)
- Juliana C. Costa-Madeira
- Department of Biochemistry and Immunology, Ribeirão Preto Medical School, University from São Paulo, Ribeirão Preto, Brazil
| | - Gabrielly B. Trindade
- Department of Biochemistry and Immunology, Ribeirão Preto Medical School, University from São Paulo, Ribeirão Preto, Brazil
| | - Paulo H. P. Almeida
- Department of Biochemistry and Immunology, Ribeirão Preto Medical School, University from São Paulo, Ribeirão Preto, Brazil
| | - João S. Silva
- Department of Biochemistry and Immunology, Ribeirão Preto Medical School, University from São Paulo, Ribeirão Preto, Brazil
- Fiocruz-Bi-Institutional Translational Medicine Project, Ribeirão Preto, Brazil
| | - Vanessa Carregaro
- Department of Biochemistry and Immunology, Ribeirão Preto Medical School, University from São Paulo, Ribeirão Preto, Brazil
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Nagase N, Ikeda Y, Tsuji A, Kitagishi Y, Matsuda S. Efficacy of probiotics on the modulation of gut microbiota in the treatment of diabetic nephropathy. World J Diabetes 2022; 13:150-160. [PMID: 35432750 PMCID: PMC8984564 DOI: 10.4239/wjd.v13.i3.150] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/05/2021] [Revised: 05/21/2021] [Accepted: 02/13/2022] [Indexed: 02/06/2023] Open
Abstract
Diabetic nephropathy (DN) is a major cause of end-stage renal disease, and therapeutic options for preventing its progression are insufficient. The number of patients with DN has been increasing in Asian countries because of westernization of dietary lifestyle, which may be associated with the following changes in gut microbiota. Alterations in the gut microbiota composition can lead to an imbalanced gastrointestinal environment that promotes abnormal production of metabolites and/or inflammatory status. Functional microenvironments of the gut could be changed in the different stages of DN. In particular, altered levels of short chain fatty acids, D-amino acids, and reactive oxygen species biosynthesis in the gut have been shown to be relevant to the pathogenesis of the DN. So far, evidence suggests that the gut microbiota may play a key role in determining networks in the development of DN. Interventions directing the gut microbiota deserve further investigation as a new protective therapy in DN. In this review, we discuss the potential roles of the gut microbiota and future perspectives in the protection and/or treatment of kidneys.
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Affiliation(s)
- Nozomi Nagase
- Department of Food Science and Nutrition, Nara Women's University, Nara 630-8506, Japan
| | - Yuka Ikeda
- Department of Food Science and Nutrition, Nara Women's University, Nara 630-8506, Japan
| | - Ai Tsuji
- Department of Food Science and Nutrition, Nara Women's University, Nara 630-8506, Japan
| | - Yasuko Kitagishi
- Department of Food Science and Nutrition, Nara Women's University, Nara 630-8506, Japan
| | - Satoru Matsuda
- Department of Food Science and Nutrition, Nara Women's University, Nara 630-8506, Japan
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Abstract
Exhausted CD8 T (Tex) cells are a distinct cell lineage that arise during chronic infections and cancers in animal models and humans. Tex cells are characterized by progressive loss of effector functions, high and sustained inhibitory receptor expression, metabolic dysregulation, poor memory recall and homeostatic self-renewal, and distinct transcriptional and epigenetic programs. The ability to reinvigorate Tex cells through inhibitory receptor blockade, such as αPD-1, highlights the therapeutic potential of targeting this population. Emerging insights into the mechanisms of exhaustion are informing immunotherapies for cancer and chronic infections. However, like other immune cells, Tex cells are heterogeneous and include progenitor and terminal subsets with unique characteristics and responses to checkpoint blockade. Here, we review our current understanding of Tex cell biology, including the developmental paths, transcriptional and epigenetic features, and cell intrinsic and extrinsic factors contributing to exhaustion and how this knowledge may inform therapeutic targeting of Tex cells in chronic infections, autoimmunity, and cancer.
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Affiliation(s)
- Laura M McLane
- Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA; .,Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.,Parker Institute for Cancer Immunotherapy, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA
| | - Mohamed S Abdel-Hakeem
- Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA; .,Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.,Parker Institute for Cancer Immunotherapy, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.,Department of Microbiology and Immunology, Faculty of Pharmacy, Cairo University, Kasr El-Aini, Cairo 11562, Egypt
| | - E John Wherry
- Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA; .,Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.,Parker Institute for Cancer Immunotherapy, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA
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Nakade Y, Iwata Y, Furuichi K, Mita M, Hamase K, Konno R, Miyake T, Sakai N, Kitajima S, Toyama T, Shinozaki Y, Sagara A, Miyagawa T, Hara A, Shimizu M, Kamikawa Y, Sato K, Oshima M, Yoneda-Nakagawa S, Yamamura Y, Kaneko S, Miyamoto T, Katane M, Homma H, Morita H, Suda W, Hattori M, Wada T. Gut microbiota-derived D-serine protects against acute kidney injury. JCI Insight 2018; 3:97957. [PMID: 30333299 DOI: 10.1172/jci.insight.97957] [Citation(s) in RCA: 112] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2017] [Accepted: 08/03/2018] [Indexed: 12/11/2022] Open
Abstract
Gut microbiota-derived metabolites play important roles in health and disease. D-amino acids and their L-forms are metabolites of gut microbiota with distinct functions. In this study, we show the pathophysiologic role of D-amino acids in association with gut microbiota in humans and mice with acute kidney injury (AKI). In a mouse kidney ischemia/reperfusion model, the gut microbiota protected against tubular injury. AKI-induced gut dysbiosis contributed to the altered metabolism of D-amino acids. Among the D-amino acids, only D-serine was detectable in the kidney. In injured kidneys, the activity of D-amino acid oxidase was decreased. Conversely, the activity of serine racemase was increased. The oral administration of D-serine mitigated the kidney injury in B6 mice and D-serine-depleted mice. D-serine suppressed hypoxia-induced tubular damage and promoted posthypoxic tubular cell proliferation. Finally, the D-serine levels in circulation were significantly correlated with the decrease in kidney function in AKI patients. These results demonstrate the renoprotective effects of gut-derived D-serine in AKI, shed light on the interactions between the gut microbiota and the kidney in both health and AKI, and highlight D-serine as a potential new therapeutic target and biomarker for AKI.
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Affiliation(s)
| | - Yasunori Iwata
- Division of Infection Control.,Division of Nephrology, and
| | - Kengo Furuichi
- Division of Nephrology, and.,Division of Blood Purification, Kanazawa University, Kanazawa, Ishikawa, Japan
| | | | - Kenji Hamase
- Graduate School of Pharmaceutical Sciences, Kyushu University, Higashi-ku, Fukuoka, Japan
| | - Ryuichi Konno
- Department of Pharmaceutical Sciences, International University of Health and Welfare, Ohtawara, Tochigi, Japan
| | | | | | | | | | | | | | | | | | | | | | | | | | | | | | - Shuichi Kaneko
- Department of System Biology, Kanazawa University, Kanazawa, Ishikawa, Japan
| | - Tetsuya Miyamoto
- Laboratory of Biomolecular Science, Graduate School of Pharmaceutical Sciences, Kitasato University, Minato-ku, Tokyo, Japan
| | - Masumi Katane
- Laboratory of Biomolecular Science, Graduate School of Pharmaceutical Sciences, Kitasato University, Minato-ku, Tokyo, Japan
| | - Hiroshi Homma
- Laboratory of Biomolecular Science, Graduate School of Pharmaceutical Sciences, Kitasato University, Minato-ku, Tokyo, Japan
| | - Hidetoshi Morita
- Graduate School of Environmental and Life Science, Okayama University, Tsushima-naka, Okayama, Japan
| | - Wataru Suda
- RIKEN Center for Integrative Medical Sciences, Yokohama, Kanagawa, Japan.,Graduate School of Frontier Sciences, The University of Tokyo, Kashiwa, Chiba, Japan
| | - Masahira Hattori
- Graduate School of Frontier Sciences, The University of Tokyo, Kashiwa, Chiba, Japan.,Graduate School of Advanced Science and Engineering, Waseda University, Shinjyuku-ku, Tokyo, Japan
| | - Takashi Wada
- Department of Nephrology and Laboratory Medicine.,Division of Nephrology, and
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