T follicular helper(Tfh)cells are crucial for regulating autoimmune inflammation and protective immunity against viral infection.However,the molecular mechanism controlling Tfh cell differentiation is poorly understoo...T follicular helper(Tfh)cells are crucial for regulating autoimmune inflammation and protective immunity against viral infection.However,the molecular mechanism controlling Tfh cell differentiation is poorly understood.Here,through two mixed bone marrow chimeric experiments,we identified Peli1,a T cell-enriched E3 ubiquitin ligase,as an intrinsic regulator that inhibits Tfh cell differentiation.Peli1 deficiency significantly promoted c-Rel-mediated inducible T-cell costimulator(ICOS)expression,and PELI1 mRNA expression was negatively associated with ICOS expression on human CD4^(+)T cells.Mechanistically,increased ICOS expression on Peli1-KO CD4^(+)T cells enhanced the activation of PI3K-AKT signaling and thus suppressed the expression of Klf2,a transcription factor that inhibits Tfh differentiation.Therefore,reconstitution of Klf2 abolished the differences in Tfh differentiation and germinal center reaction between WT and Peli1-KO cells.As a consequence,Peli1-deficient CD4^(+)T cells promoted lupus-like autoimmunity but protected against H1N1 influenza virus infection in mouse models.Collectively,our findings established Peli1 as a critical negative regulator of Tfh differentiation and indicated that targeting Peli1 may have beneficial therapeutic effects in Tfhrelated autoimmunity or infectious diseases.展开更多
基金supported by grants from the National Key R&D Program of China(2018YFA0107201,2018YFA0902703)the National Natural Science Foundation of China(82030041,81770567)+4 种基金the Strategic Priority Research Program of the Chinese Academy of Sciences(XDB39030300)the Program of Shanghai Academic/Technology Research Leader(20XD1424600)the Key Research Program of the Chinese Academy of Sciences(CAS)(KFZD-SW-216)the Thousand Young Talents Plan of Chinathe CAS Key Laboratory of Tissue Microenvironment and Tumor.
文摘T follicular helper(Tfh)cells are crucial for regulating autoimmune inflammation and protective immunity against viral infection.However,the molecular mechanism controlling Tfh cell differentiation is poorly understood.Here,through two mixed bone marrow chimeric experiments,we identified Peli1,a T cell-enriched E3 ubiquitin ligase,as an intrinsic regulator that inhibits Tfh cell differentiation.Peli1 deficiency significantly promoted c-Rel-mediated inducible T-cell costimulator(ICOS)expression,and PELI1 mRNA expression was negatively associated with ICOS expression on human CD4^(+)T cells.Mechanistically,increased ICOS expression on Peli1-KO CD4^(+)T cells enhanced the activation of PI3K-AKT signaling and thus suppressed the expression of Klf2,a transcription factor that inhibits Tfh differentiation.Therefore,reconstitution of Klf2 abolished the differences in Tfh differentiation and germinal center reaction between WT and Peli1-KO cells.As a consequence,Peli1-deficient CD4^(+)T cells promoted lupus-like autoimmunity but protected against H1N1 influenza virus infection in mouse models.Collectively,our findings established Peli1 as a critical negative regulator of Tfh differentiation and indicated that targeting Peli1 may have beneficial therapeutic effects in Tfhrelated autoimmunity or infectious diseases.
