Autoantigen-specific CD4^(+)T cells are central to the development of autoimmune diseases,while the expansion of regulatory T(Treg)cells expressing Forkhead box protein 3(Foxp3)is essential for mitigating these condit...Autoantigen-specific CD4^(+)T cells are central to the development of autoimmune diseases,while the expansion of regulatory T(Treg)cells expressing Forkhead box protein 3(Foxp3)is essential for mitigating these conditions.In this study,we identified CD4^(+)Notch^(2+)Foxp3^(lo) T cells in the spinal cords of mice with experimental autoimmune encephalomyelitis(EAE),dextran sodium sulfate-induced colitis model mice,and patients with ulcerative colitis as immune regulatory cells.These cells exhibited a nonproliferative,dysfunctional phenotype and demonstrated immune regulatory functions,including suppressive activity against activated CD4^(+)T cells and marked Treg cell expansion activity.Our data revealed that Notch2 deletion in Foxp3-expressing cells diminishes the ability of this population to reverse the clinical symptoms of EAE.Collectively,these findings suggest that Notch2 expression in dysfunctional CD4^(+)T cells plays a crucial role in immune regulation.展开更多
During T-cell-mediated inflammatory responses,T cells are activated upon recognizing specific antigens presented by antigenpresenting cells.This recognition initiates signaling through the TCR and CD28,leading to thei...During T-cell-mediated inflammatory responses,T cells are activated upon recognizing specific antigens presented by antigenpresenting cells.This recognition initiates signaling through the TCR and CD28,leading to their activation and subsequent clonal expansion.Within the signaling cascades triggered by TCR and CD28 engagement,the CD28-PI3K pathway serves as a central regulator of metabolic reprogramming in T cells,supporting the biosynthetic needs essential for their effective proliferation.In this study,we found that the regulation of PANK4 plays a role in TCR/CD28-mediated CD4^(+)T-cell proliferation by regulating de novo lipid synthesis.The CD28 signaling pathway negatively regulates PANK4 through direct binding with PDK1,thereby controlling de novo lipid synthesis for CD4^(+)T-cell proliferation.Interestingly,we found that Pank4-deficient CD4^(+)T cells enhance coenzyme A synthesis and glutaminolysis,whereby glutamine contributes carbon for fatty acid synthesis and provides nitrogen for coenzyme A biosynthesis.The regulatory role of PANK4 in CD4^(+)T-cell proliferation was confirmed in models of experimental colitis and influenza A virus infection,where Pank4-deficient CD4^(+)T cells exhibited greater expansion than their wild-type counterparts when co-transferred.Our findings suggest that PANK4 regulation of de novo lipid synthesis is crucial for TCR/CD28-induced CD4^(+)T-cell proliferation and represents a potential target for modulating general CD4^(+)T-cell responses.展开更多
基金supported by the National Research Foundation of Korea(NRF-2021R1A2C3011211,NRF-2022M3A9I2017587).Open Access funding enabled and organized by Seoul National University.
文摘Autoantigen-specific CD4^(+)T cells are central to the development of autoimmune diseases,while the expansion of regulatory T(Treg)cells expressing Forkhead box protein 3(Foxp3)is essential for mitigating these conditions.In this study,we identified CD4^(+)Notch^(2+)Foxp3^(lo) T cells in the spinal cords of mice with experimental autoimmune encephalomyelitis(EAE),dextran sodium sulfate-induced colitis model mice,and patients with ulcerative colitis as immune regulatory cells.These cells exhibited a nonproliferative,dysfunctional phenotype and demonstrated immune regulatory functions,including suppressive activity against activated CD4^(+)T cells and marked Treg cell expansion activity.Our data revealed that Notch2 deletion in Foxp3-expressing cells diminishes the ability of this population to reverse the clinical symptoms of EAE.Collectively,these findings suggest that Notch2 expression in dysfunctional CD4^(+)T cells plays a crucial role in immune regulation.
基金supported by grants from the National Research Foundation of Korea(grant numbers:NRF-2021R1A2C3011211,NRF-2022M3A9I2017587,and NRF-2022R1C1C1003619)Creative-Pioneering Researchers Program(grant number:370-2024114)from Seoul National University,the Ministry of Food and Drug Safety in Korea(grant number:RS-2024-00331849)Ascending SNU Future Leader Fellowship through Seoul National University.
文摘During T-cell-mediated inflammatory responses,T cells are activated upon recognizing specific antigens presented by antigenpresenting cells.This recognition initiates signaling through the TCR and CD28,leading to their activation and subsequent clonal expansion.Within the signaling cascades triggered by TCR and CD28 engagement,the CD28-PI3K pathway serves as a central regulator of metabolic reprogramming in T cells,supporting the biosynthetic needs essential for their effective proliferation.In this study,we found that the regulation of PANK4 plays a role in TCR/CD28-mediated CD4^(+)T-cell proliferation by regulating de novo lipid synthesis.The CD28 signaling pathway negatively regulates PANK4 through direct binding with PDK1,thereby controlling de novo lipid synthesis for CD4^(+)T-cell proliferation.Interestingly,we found that Pank4-deficient CD4^(+)T cells enhance coenzyme A synthesis and glutaminolysis,whereby glutamine contributes carbon for fatty acid synthesis and provides nitrogen for coenzyme A biosynthesis.The regulatory role of PANK4 in CD4^(+)T-cell proliferation was confirmed in models of experimental colitis and influenza A virus infection,where Pank4-deficient CD4^(+)T cells exhibited greater expansion than their wild-type counterparts when co-transferred.Our findings suggest that PANK4 regulation of de novo lipid synthesis is crucial for TCR/CD28-induced CD4^(+)T-cell proliferation and represents a potential target for modulating general CD4^(+)T-cell responses.
