Cytotoxic T lymphocyte-associated protein 4(CTLA-4)plays a crucial role in maintaining peripheral immune tolerance,but its mechanisms of action are highly complicated.Here,through the generation of a gene knock-in(KI)...Cytotoxic T lymphocyte-associated protein 4(CTLA-4)plays a crucial role in maintaining peripheral immune tolerance,but its mechanisms of action are highly complicated.Here,through the generation of a gene knock-in(KI)mouse carrying a CTLA-4 Y139C human patient-derived pathogenic mutation,we phenocopied the lethal autoimmune diseases in Ctla4 KO mice due to the impairment of Treg functions.Interestingly,although both KO and KI Treg cells lost the ability to endocytose B7 molecules,the KO and KI mice differed in terms of T-cell proliferation since the KI mutation retained its ability to transmit inhibitory signals.Therefore,this study not only dissected the two distinct immunoregulatory mechanisms of CTLA-4 but also provided genetic evidence highlighting the importance of ligand trans-endocytosis in the function of CTLA-4.Our findings enhance our understanding of CTLA-4 function and CTLA-4 insufficiency disease,providing valuable insights for advancing improved immunotherapy strategies targeting CTLA-4.展开更多
Protein phosphatase 2A(PP2A)is one of the most abundant serine/threonine phosphatases and plays critical roles in regulating cell fate and function.We previously showed that PP2A regulates the differentiation of CD4^(...Protein phosphatase 2A(PP2A)is one of the most abundant serine/threonine phosphatases and plays critical roles in regulating cell fate and function.We previously showed that PP2A regulates the differentiation of CD4^(+)T cells and the development of thymocytes.Nevertheless,its role in CD8^(+)T cells remains elusive.By ablating the catalytic subunit α(Cα)of PP2A in CD8^(+)T cells,we revealed the essential role of PP2A in promoting the effector functions of CD8^(+)T cells.Notably,PP2A Cα-deficient CD8^(+)T cells exhibit reduced proliferation and decreased cytokine production upon stimulation in vitro.In vivo,mice lacking PP2A Cαin T cells displayed defective immune responses against lymphocytic choriomeningitis virus infection,associated with reduced CD8^(+)T cell expansion and decreased cytokine production.Consistently,the ablation of the PP2A Cαsubunit in CD8^(+)T cells results in attenuated antitumor activity in mice.There is a notable decrease in the infiltration of PP2A Cα-deficient CD8^(+)T cells within the tumor microenvironment,and the cells that do infiltrate exhibit diminished effector functions.Mechanistically,PP2A Cα deficiency impedes CD28-induced AKT Ser^(473) phosphorylation,thus impairing CD8^(+)T cell costimulation signal.Collectively,our findings underscore the critical role of phosphatase PP2A as a propeller for CD28-mediated costimulation signaling in CD8^(+)T cell effector function by fine-tuning T cell activation.展开更多
基金supported by National Natural Science Foundation of China Grants 31930038,U21A20199,32141004,and 32350007(to LL)an innovative research team of high-level local universities in Shanghai SHSMU-ZLCX 20211600(to LL)+1 种基金the Provincial Natural Science Foundation of Zhejiang Province LQ22H030012China Postdoctoral Science Foundation 2022M720087(to KXZ).
文摘Cytotoxic T lymphocyte-associated protein 4(CTLA-4)plays a crucial role in maintaining peripheral immune tolerance,but its mechanisms of action are highly complicated.Here,through the generation of a gene knock-in(KI)mouse carrying a CTLA-4 Y139C human patient-derived pathogenic mutation,we phenocopied the lethal autoimmune diseases in Ctla4 KO mice due to the impairment of Treg functions.Interestingly,although both KO and KI Treg cells lost the ability to endocytose B7 molecules,the KO and KI mice differed in terms of T-cell proliferation since the KI mutation retained its ability to transmit inhibitory signals.Therefore,this study not only dissected the two distinct immunoregulatory mechanisms of CTLA-4 but also provided genetic evidence highlighting the importance of ligand trans-endocytosis in the function of CTLA-4.Our findings enhance our understanding of CTLA-4 function and CTLA-4 insufficiency disease,providing valuable insights for advancing improved immunotherapy strategies targeting CTLA-4.
基金supported by the China Postdoctoral Science Foundation(2022M720087 to K.Z.)National Natural Science Foundation of China(32300775 to K.Z.,32100718 to X.J.,32141004,32350007,and 31930038 to L.L.)+2 种基金the Provincial Natural Science Foundation of Zhejiang Province(LQ22H030012 to S.H.)the Huadong Medicine Joint Funds of the Zhejiang Provincial Natural Science Foundation of China(LHDMZ24H310001 to X.J.)the Scientific Research Fund of Zhejiang Provincial Education Department(Y202146347 to X.J.).
文摘Protein phosphatase 2A(PP2A)is one of the most abundant serine/threonine phosphatases and plays critical roles in regulating cell fate and function.We previously showed that PP2A regulates the differentiation of CD4^(+)T cells and the development of thymocytes.Nevertheless,its role in CD8^(+)T cells remains elusive.By ablating the catalytic subunit α(Cα)of PP2A in CD8^(+)T cells,we revealed the essential role of PP2A in promoting the effector functions of CD8^(+)T cells.Notably,PP2A Cα-deficient CD8^(+)T cells exhibit reduced proliferation and decreased cytokine production upon stimulation in vitro.In vivo,mice lacking PP2A Cαin T cells displayed defective immune responses against lymphocytic choriomeningitis virus infection,associated with reduced CD8^(+)T cell expansion and decreased cytokine production.Consistently,the ablation of the PP2A Cαsubunit in CD8^(+)T cells results in attenuated antitumor activity in mice.There is a notable decrease in the infiltration of PP2A Cα-deficient CD8^(+)T cells within the tumor microenvironment,and the cells that do infiltrate exhibit diminished effector functions.Mechanistically,PP2A Cα deficiency impedes CD28-induced AKT Ser^(473) phosphorylation,thus impairing CD8^(+)T cell costimulation signal.Collectively,our findings underscore the critical role of phosphatase PP2A as a propeller for CD28-mediated costimulation signaling in CD8^(+)T cell effector function by fine-tuning T cell activation.
