Regulatory T(T_(reg))cells play an essential role in maintaining immune balance across various physiological and pathological conditions.However,the mechanisms underlying T_(reg)homeostasis remain incompletely underst...Regulatory T(T_(reg))cells play an essential role in maintaining immune balance across various physiological and pathological conditions.However,the mechanisms underlying T_(reg)homeostasis remain incompletely understood.Here,we report that RIPK1 is crucial for T_(reg) cell survival and homeostasis.We generated mice with T_(reg) cell-specific ablation of Ripk1 and found that these mice developed fatal systemic autoimmunity due to a dramatic reduction in the Treg cell compartment caused by excessive cell death.Unlike conventional T cells,Treg cells with Ripk1 deficiency were only partially rescued from cell death by blocking FADD-dependent apoptosis.However,simultaneous removal of both Fadd and Ripk3 completely restored the homeostasis of Ripk1-deficient Treg cells by blocking two cell death pathways.Thus,our study highlights the critical role of RIPK1 in regulating Treg cell homeostasis by controlling both apoptosis and necroptosis,thereby providing novel insights into the mechanisms of Treg cell homeostasis.展开更多
基金supported by the following grants:National Key Research and Development Program of China(2021YFA1301402)Shanghai Municipal Science and Technology Major Project(ZD2021CY001)+5 种基金National Key Research and Development Program of China(2021YFE02009002022YFA0807300)National Natural Science Foundation of China(82101833,82073901)Three-year Action Plan for Shanghai TCM Development and Inheritance Program[ZY(2021-2023)-0103]Top-level Clinical Discipline Project of Shanghai Pudong District(grant/award number:PWYgf 2021-01)Training Plan for Discipline Leaders of Shanghai Pudong New Area Health Commission(grant/award number:PWRd2020-09).
文摘Regulatory T(T_(reg))cells play an essential role in maintaining immune balance across various physiological and pathological conditions.However,the mechanisms underlying T_(reg)homeostasis remain incompletely understood.Here,we report that RIPK1 is crucial for T_(reg) cell survival and homeostasis.We generated mice with T_(reg) cell-specific ablation of Ripk1 and found that these mice developed fatal systemic autoimmunity due to a dramatic reduction in the Treg cell compartment caused by excessive cell death.Unlike conventional T cells,Treg cells with Ripk1 deficiency were only partially rescued from cell death by blocking FADD-dependent apoptosis.However,simultaneous removal of both Fadd and Ripk3 completely restored the homeostasis of Ripk1-deficient Treg cells by blocking two cell death pathways.Thus,our study highlights the critical role of RIPK1 in regulating Treg cell homeostasis by controlling both apoptosis and necroptosis,thereby providing novel insights into the mechanisms of Treg cell homeostasis.
基金This work was supported by grants from the National Key Basic Research Program of China （2010CB529901 and 2010CB530600）, the National Natural Science Foundation of China （31100619 and 30972705）, the China Postdoctoral Science Foundation （20110490186）, the Chen-guang Plan Project of Shanghai Educational Municipal Education Commission （11CG48 and szyl0004）, the Specialized Research Fund for the Doctoral Program of Higher Education （20113107120014） and the Leading Academic Discipline Project of Shanghai Municipal Education Commission （J50301） （Yuejuan Zheng, Shanghai University of T.C.M）.
