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Id2 epigenetically controls CD8^(+)t-cell exhaustion by disrupting the assembly of the tcf3-LSD1 complex

cellular & Molecular Immunology 2024年第3期21卷 292-308页

作者： Yiming Li Mingwei Han Haolin Wei Wan Huang Zhinan Chen tianjiao Zhang Meirui Qian Lin Jing Gang Nan Xiuxuan Sun Shuhui Dai Kun Wang Jianli Jiang Ping Zhu Liang Chen Department of cell Biology of National translational Science Center for Molecular Medicine and Department of Clinical Immunology of Xijing Hospital Fourth Military Medical UniversityXi’anShaanxi 710032China State Key Laboratory of New targets Discovery and Drug Development for Major Diseases GanzhouJiangxi341000Xi’anShaanxi 710032China School of Medicine Shanghai UniversityShanghai 200444China

CD8^(+)t-cell exhaustion is a state of dysfunction that promotes tumor progression and is marked by the generation of Slamf6^(+)progenitor exhausted(tex^(prog))and tim-^(3+)terminally exhausted(tex^(term))*** of DNA binding protein 2(Id2)has been shown to play important roles in t-cell development and CD8^(+)t-cell ***,the role of Id2 in CD8^(+)t-cell exhaustion is ***,we found that Id2 transcriptionally and epigenetically regulates the generation of texprog cells and their conversion to texterm *** deletion of Id2 dampens CD8^(+)t-cell-mediated immune responses and the maintenance of stem-like CD8^(+)t-cell subpopulations,suppresses PD-1 blockade and increases tumor ***,through its HLH domain,Id2 binds and disrupts the assembly of the tcf3-tal1 transcriptional regulatory complex,and thus modulates chromatin accessibility at the Slamf6 promoter by preventing the interaction of tcf3 with the histone lysine demethylase ***,Id2 increases the abundance of the permissive H3K4me2 mark on the tcf3-occupied E-boxes in the Slamf6 promoter,modulates chromatin accessibility at the Slamf6 promoter and epigenetically regulates the generation of Slamf6+texprog *** LSD1 inhibitor GSK2879552 can rescue the Id2 knockout phenotype in tumor-bearing *** of LSD1 increases the abundance of Slamf6^(+)tim-3^(−)tex^(prog) cells in tumors and the expression level of tcf1 in Id2-deleted CD8+t *** study demonstrates that Id2-mediated transcriptional and epigenetic modification drives hierarchical CD8^(+)t-cell exhaustion,and the mechanistic insights gained may have implications for therapeutic intervention with tumor immune evasion.

关键词： Id2 t-cell exhaustion Epigenetic modification Immune evasion

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Glycogen synthase kinase 3 controls t-cell exhaustion by regulating NFAt activation

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cellular & Molecular Immunology 2023年第10期20卷 1127-1139页

作者： Yubing Fu Jinjia Wang Chenfeng Liu Kunyu Liao Xianjun Gao Ronghan tang Binbin Fan Yazhen Hong Nengming Xiao Changchun Xiao Wen-Hsien Liu State Key Laboratory of cellular Stress Biology School of Life SciencesFaculty of Medicine and Life ScienceXiamen UniversityXiamen361102FujianChina Department of cell Biology School of Life ScienceAnhui Medical UniversityHefei230031AnhuiChina Sanof institute for Biomedical Research SuzhouJiangsu 215123 China.

cellular immunity mediated by CD8+t cells plays an indispensable role in bacterial and viral clearance and ***,persistent antigen stimulation of CD8+t cells leads to an exhausted or dysfunctional cellular state characterized by the loss of effector function and high expression of inhibitory receptors during chronic viral infection and in *** studies have shown that glycogen synthase kinase 3(GSK3)controls the function and development of immune cells,but whether GSK3 affects CD8+t cells is not clearly ***,we demonstrate that mice with deletion of Gsk3αand Gsk3βin activated CD8+t cells(DKO)exhibited decreased CtL differentiation and effector function during acute and chronic viral *** addition,DKO mice failed to control tumor growth due to the upregulated expression of inhibitory receptors and augmented t-cell exhaustion in tumor-infiltrating CD8+t ***,anti-PD-1 immunotherapy substantially restored tumor rejection in DKO ***,GSK3 regulates t-cell exhaustion by suppressing tCR-induced nuclear import of NFAt,thereby in turn dampening NFAt-mediated exhaustion-related gene expression,including tOX/tOX2 and ***,we uncovered the molecular mechanisms underlying GSK3 regulation of CtL differentiation and t-cell exhaustion in anti-tumor immune responses.

关键词： GSK3 t-cell exhaustion Viral infection Anti-tumor immunity Inhibitory receptors

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Is modification of mitochondrial metabolism a promising strategy for reversing t-cell exhaustion in tumor microenviroment?

Is modification of mitochondrial metabolism a promising stra...

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第十一届全国免疫学学术大会

作者： Ren Laifeng Su Wen Shanxi Provincial tumor Hospital

Objective: In this paper, we overview the updated publications to understand the relationship between t-cell exhaustion and mitochondrial disorders in the tumor microenvironment, and to explore its potential application of immunotherapy to tumor. Methods: Relevant published papers and abstracts were retrieved by using the electronic databases and all the documents were reviewed. Results: Recent studies showed that the exhausted t cells can be reinvigorated in several ways, including chimeric antigen receptor t-cell(CAR-t) therapy, anti-PD-1 and anti-CtLA-4 antibodies-mediated blockade of immune checkpoint, and so on. Although these approaches has achieved inspiring results in the treatment to various cancers, the majority of patients still do not respond to these therapies efficiently. It is known that metabolism is central to cellular function and recent studies suggested that mitochondrial metabolism could determine the fate and function of t cells. Encouragingly,two studies published in Immunity in 2016 showed that in chronic viral infections and cancer, the dysfunctional mitochondrial metabolism caused by perturbed mtOR or Akt signal can result in t-cell *** of the key regulator of mitochondrial biogenesis, PGC1α, may rescues t cell functionality, revealing the regulation of cellular metabolism as a promising strategy for the tumor immunotherapy. Conclusion: In summary, current studies suggest that:(1) t-cell exhaustion can be reversed by appropriate approach;(2) Mitochondrial metabolism of t cells is likely a key target in the next generation of immunotherapy to cancer;(3) Combined treatments with the modification of mitochondrial metabolism and the blockade of immune checkpoint in t cells could be a promising strategy to improve the therapeutic outcome of cancers, especially those resistant to the checkpoint inhibition therapy.(4) the regulation of mitochondrial metabolism of t cells may hopefully become the basis for evaluating the thera

关键词： t-cell exhaustion tumor microenvironment immunotherapy mitochondria metabolism

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the combination of PD-1 blockade with interferon-αhas a synergistic effect on hepatocellular carcinoma

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cellular & Molecular Immunology 2022年第6期19卷 726-737页

作者： Ying Zhu Mo Chen Da Xu tian-En Li Ze Zhang Jian-Hua Li Xiang-Yu Wang Xin Yang Lu Lu Hu-Liang Jia Qiong-Zhu Dong Lun-Xiu Qin Department of General Surgery Huashan HospitalCancer Metastasis InstituteFudan University12 Urumqi Road(M)Shanghai 200040China institutes of Biomedical Sciences Fudan University131 Dong An RoadShanghai 200032China

Background the efficacy of immune checkpoint inhibitors(ICIs),such as programmed cell death protein-1(PD-1)or its ligand 1(PD-L1)antibody,in hepatocellular carcinoma(HCC)is limited,and it is recommended that they be combined with other *** evaluated the combination of pegylated interferon-α(Peg-IFNα)with PD-1 blockade in HCC mouse *** We analyzed the effects of Peg-IFNαon tumor-infiltrating immune cells and PD-1 expression in the HCC immune microenvironment and examined the underlying mechanism of its unique effect on the PD-1 *** in vivo efficacy of anti-PD-1 and Peg-IFNαwas evaluated in both subcutaneous and orthotopic mouse models of *** the combination of Peg-IFNαwith PD-1 blockade dramatically enhanced t-cell infiltration,improved the efficacy of PD-1 antibody and prolonged mouse survival compared with PD-1 antibody ***,Peg-IFNαcould recruit cytotoxic CD8+t cells to infiltrate the HCC microenvironment by inducing tumor cells to secrete the chemokine ***,the HCC microenvironment quickly overcame the immune responses by upregulating PD-1 expression in CD8+t cells via the IFNα-IFNAR1-JAK1-StAt3 signaling *** combination of PD-1 blockade with Peg-IFNαcould restore the cytotoxic capacity of CD8+t cells and exerted a significant synergistic effect on *** these results indicate that in addition to initiating the antitumor immune response itself,Peg-IFNαcan also generate a microenvironment favoring PD-1 ***,the combination of Peg-IFNαand PD-1 blockade can be a promising strategy for HCC.

关键词： Hepatocellular carcinoma tumor microenvironment PD-1 Pegylated interferon-α t-cell exhaustion

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Regulation of CD8^(+)t memory and exhaustion by the mtOR signals

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cellular & Molecular Immunology 2023年第9期20卷 1023-1039页

作者： Yao Chen Ziyang Xu Hongxiang Sun Xinxing Ouyang Yuheng Han Haihui Yu Ningbo Wu Yiting Xie Bing Su Shanghai Institute of Immunology Department of Immunology and Microbiologyand The Ministry of Education Key Laboratory of Cell Death and DifferentiationShanghai Jiao Tong University School of MedicineShanghai 200025China Department of tumor Biology Shanghai Chest HospitalShanghai Jiao Tong University School of MedicineShanghai 200025China Center for Immune-Related Diseases at Shanghai Institute of Immunology Department of GastroenterologyRuijin HospitalShanghai Jiao Tong University School of MedicineShanghai 200025China Shanghai Jiao tong University School of Medicine–Yale Institute for Immune Metabolism Shanghai Jiao Tong University School of MedicineShanghaiChina Key Laboratory of Molecular Radiation Oncology of Hunan Province Xiangya HospitalCentral South UniversityChangshaChina

CD8^(+)t cells are the key executioners of the adaptive immune arm,which mediates antitumor and antiviral ***ïve CD8^(+)t cells develop in the thymus and are quickly activated in the periphery after encountering a cognate antigen,which induces these cells to proliferate and differentiate into effector cells that fight the initial ***,a fraction of these cells become long-lived memory CD8^(+)t cells that combat future ***,the generation and maintenance of memory cells is profoundly affected by various in vivo conditions,such as the mode of primary activation(e.g.,acute *** immunization)or fluctuations in host metabolic,inflammatory,or aging ***,many t cells may be lost or become exhausted and no longer *** intracellular signaling pathways,transcription factors,epigenetic modifications,and metabolic processes are involved in this ***,understanding the cellular and molecular basis for the generation and fate of memory and exhausted CD8^(+)cells is central for harnessing cellular *** this review,we focus on mammalian target of rapamycin(mtOR),particularly signaling mediated by mtOR complex(mtORC)2 in memory and exhausted CD8^(+)t cells at the molecular level.

关键词： mtOR Sin1 CD8^(+)t cell t-cell memory t-cell exhaustion

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tumor-expressed B7-H3 mediates the inhibition of antitumor t-cell functions in ovarian cancer insensitive to PD-1 blockade therapy

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cellular & Molecular Immunology 2020年第3期17卷 227-236页

作者： Dongli Cai Jiaming Li Dingfeng Liu Shanjuan Hong Qin Qiao Qinli Sun Pingping Li Nanan Lyu tiantian Sun Shan Xie Li Guo Ling Ni Liping Jin Chen Dong Obstetrics&Gynecology Hospital Fudan UniversityShanghai 200011China Institute for Immunology and School of Medicine Tsinghua UniversityBeijing 100084China Suzhou Kanova Biopharmaceutical Co. LtdSuzhou 215000China Clinical and translational Research Center Shanghai First Maternity and Infant HospitalTongji University School of MedicineShanghai 201204China Department of Gynecologic Oncology Beijing Obstetrics and Gynecology HospitalCapital Medical UniversityBeijingChina Beijing Key Lab for Immunological Research on Chronic Diseases Beijing 100084China

Although PD-L1/PD-1 blockade therapy has been approved to treat many types of cancers,the majority of patients with solid tumors do not respond well,but the underlying reason remains ***,we studied ovarian cancer(OvCa),a tumor type generally resistant to current immunotherapies,to investigate PD-1-independent *** found that PD-L1 was not highly expressed in the tumor microenvironment(tME)of human ***,B7-H3,another checkpoint molecule,was highly expressed by both tumor cells and tumor-infiltrating antigen-presenting cells(APCs),which correlated with t-cell exhaustion in *** ID8 OvCa mouse models,we found that B7-H3 expressed on tumor cells,but not host cells,had a dominant role in suppressing antitumor ***,B7-H3 blockade,but not PD-1 blockade,prolonged the survival of ID8 tumorbearing ***,our results demonstrate that tumor-expressed B7-H3 inhibits the function of CD8^(+)t cells and suggest that B7-H3 may be a target in patients who are not responsive to PD-L1/PD-1 inhibition,particularly OvCa patients.

关键词： Antitumor immunity Immune checkpoint B7-H3 t-cell exhaustion Ovarian cancer

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Effective intrahepatic CD8＋ t-cell immune responses are induced by low but not high numbers of antigen-expressing hepatocytes

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cellular & Molecular Immunology 2016年第6期13卷 805-815页

作者： Aaron Ochel Marcin Cebula Mathias Riehn Upneet Hillebrand Christoph Lipps Reinhold Schirmbeck Hansjorg Hauser Dagmar Wirth Model Systems for Infection and Immunity Helmholtz Centre for Infection Research Inhoffenstr. 7 38124 Braunschweig Germany Clinic for Internal Medicine I University Hospital UIm Albert-Einstein-Allee 23 89081 UIm Germany Experimental Hematology Medical School Hannover Carl-Neuberg-Str. 1 D-30625 Hannover Germany Current address Institute for Immunology Justus-Liebig University Giessen BFS Schubertstr. 81 35390 Giessen Germany

Liver infections with hepatotropic viruses, such as hepatitis B virus and hepatitis C virus are accompanied by viral persistence and immune failure. CD8＋ t cells are crucial mediators of the intrahepatic antiviral immune response. Chronic infections of the liver and other organs correlate with t-cell exhaustion. It was previously suggested that high antigen load could result in t-cell exhaustion. We aimed at elucidating the impact of different intrahepatic antigen loads on the quality of CD8＋ t-cell-mediated immunity by employing an infection-free transgenic mouse model expressing ovalbumin （Ova） as the target antigen. Adoptive transfer of Ot-I cells induced a transient intrahepatic immune response toward both high and low Ova levels. However, antigen clearance was achieved only in mice expressing low antigen levels. In contrast, t cells exposed to high antigen levels underwent exhaustion and became depleted, causing antigen persistence. Moreover, when functional t cells were exposed to high intrahepatic antigen levels, a complete transition toward exhaustion was observed. thus, this study shows that the antigen expression level in the liver correlates inversely with t-cell immunity in vivo and governs the efficiency of immune responses upon antigen presentation.

关键词： antigen load chronicity immune modulation t-cell exhaustion

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Activation or exhaustion of CD8^(+) t cells in patients with COVID-19

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cellular & Molecular Immunology 2021年第10期18卷 2325-2333页

作者： Min-Seok Rha Eui-Cheol Shin Laboratory of Immunology and Infectious Diseases Graduate School of Medical Science and EngineeringKorea Advanced Institute of Science and Technology(KAIST)DaejeonRepublic of Korea Department of Otorhinolaryngology Yonsei University College of MedicineSeoulRepublic of Korea.3 The Center for Epidemic PreparednessKAISTDaejeonRepublic of Korea

In addition to CD4^(+)t cells and neutralizing antibodies,CD8^(+)t cells contribute to protective immune responses against SARS-CoV-2 in patients with coronavirus disease 2019(COVID-19),an ongoing pandemic *** patients with COVID-19,CD8^(+)t cells exhibiting activated phenotypes are commonly observed,although the absolute number of CD8^(+)t cells is *** addition,several studies have reported an upregulation of inhibitory immune checkpoint receptors,such as PD-1,and the expression of exhaustion-associated gene signatures in CD8^(+)t cells from patients with ***,whether CD8^(+)t cells are truly exhausted during COVID-19 has been a controversial *** the present review,we summarize the current understanding of CD8^(+)t-cell exhaustion and describe the available knowledge on the phenotypes and functions of CD8^(+)t cells in the context of activation and *** also summarize recent reports regarding phenotypical and functional analyses of SARS-CoV-2-specific CD8^(+)t cells and discuss long-term SARS-CoV-2-specific CD8^(+)t-cell memory.

关键词： CD8^(+)t cell Activation t-cell exhaustion SARS-CoV-2 COVID-19

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the immune regulation of PD-1/PDL-1 axis, a potential biomarker in multiple sclerosis

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Neuroimmunology and Neuroinflammation 2020年第3期7卷 277-290页

作者： Maria teresa Cencioni Division of clinical neurology Brain Sciences departmentImperial College LondonLondon W12 0NNUK

Multiple sclerosis is an autoimmune disease characterised by a chronic inflammation within the central nervous system. In the last ten years, studies on multiple sclerosis have been concentrated on the discovery of new biomarkers of disease and potential therapeutic targets. In chronic infection or in cancer, the immune system response is faulty and maintained in a condition defined as t-cell exhaustion induced by expression of co-inhibitory receptors. the PD-1/PDL-1 pathway is demonstrated to be the main one responsible for promoting t-cell exhaustion, and immunotherapies targeting PD-1 or PDL-1 have shown beneficial clinical outcomes in several tumours and chronic diseases. Contrarily, transcriptional t-cell exhaustion signature and high expression of co-inhibitor receptor PD-1 are associated with favourable prognosis in multiple sclerosis and other autoimmune diseases. Several studies have clearly demonstrated PD-1 has a dual role in immune self-tolerance: to constrain autoreactive t cells in anergic condition and to protect the tissue from the damage caused by the activation of endogenous autoreactive t cells. Consequently, immune checkpoint inhibitor therapies that target inhibitory receptors in cancer cause an exacerbation of autoimmune diseases. this review describes the roles of the PD-1/ PDL-1 pathway in cancer and autoimmune diseases, especially in multiple sclerosis, and how manipulating PD-1 can be a therapeutic approach in multiple sclerosis.

关键词： t-cell exhaustion inhibitory checkpoints pathways PD-1/PDL-1 axis in autoimmune disease multiple sclerosis immune checkpoint inhibitor treatments multiple sclerosis biomarkers

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cell-mediated immunity to SARS-CoV-2

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Pediatric Investigation 2020年第4期4卷 281-291页

作者： Xiaolin Wang Jingang Gui Laboratory of tumor Immunology Beijing Pediatric Research InstituteBeijing Children’s HospitalCapital Medical UniversityNational Center for Children’s HealthBeijingChina

Severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)viruses spread unscrupulously virtually every corner on the planet in a very quick speed leading to an unprecedented world pandemic of COVID-19 claiming a great many of people’s *** importance has been given to the studies on the virus itself including genomic variation and viron structure,as well as cell entry pathway and tissue *** than that,to learn the main characteristic of host immunity responding to SARS-CoV-2 infection is an eminent task for restraining virus and controlling disease *** antibody production in response to SARS-CoV-2 infection,host cellular immunity plays an indispensable role in impeding virus replication and expansion at various stages of COVID-19 *** this review,we summarized the recent knowledge regarding the aberrant regulation and dysfunction of multiple immune cells during SARS-CoV-2 *** includes the dysregulation of immune cell number,th polarity,cytokine storm they implicated with,as well as cell function exhaustion after chronic virus *** that many obstacles remain to be overcome,studies on immunotherapy for COVID-19 treatment based on the known features of host immunity in response to SARS-CoV-2 infection offer us tangible benefits and hope for making this SARS-CoV-2 pandemic under control.

关键词： SARS-CoV-2 COVID-19 Innate immune t-cell exhaustion Cytokine storm Immunotherapy

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