PP6 controls T cell development and homeostasis by negatively regulating distal TCR signaling

【作者】 叶坚； 史豪； 陶无凡；

【机构】 复旦大学发育生物学研究所；

【摘要】 T cell development and homeostasis are both regulated by TCR signals.Protein phosphorylation and dephosphorylation,which are catalyzed by protein kinases and phosphatases respectively,serve as important switches controlling multiple downstream pathways triggered by TCR recognition of antigens.It is has been well documented that protein tyrosine phosphatases(PTPs)are involved in negative regulation of proximal TCR signaling.However,how TCR signals are terminated or attenuated in the distal TCR pathways is largely unknown.We investigated the function of Ser/Thr protein phosphatase 6(PP6)in TCR signaling.T cell lineage-specific ablation of PP6 in mice resulted in enhanced thymic positive and negative selection and preferential expansion of fetal-derived IL-17-producing Vγ6Vδ1~+T cells.Both PP6-deficient peripheral CD4~+helper and CD8~+cytolytic cells could not maintain a naive state and became fast-proliferating and short-lived effector cells.PP6-deficiency led to profound hyperactivation of multiple distal TCR signaling molecules,including MAPKs,AKT and NF-κB.Our studies demonstrate that PP6 acts as a critical negative regulator,not only controlling bothαβandγδlineage development but also maintaining naive T cell homeostasis by preventing their premature activation prior to antigen stimulation.更多还原

【Abstract】 T cell development and homeostasis are both regulated by TCR signals.Protein phosphorylation and dephosphorylation,which are catalyzed by protein kinases and phosphatases respectively,serve as important switches controlling multiple downstream pathways triggered by TCR recognition of antigens.It is has been well documented that protein tyrosine phosphatases(PTPs) are involved in negative regulation of proximal TCR signaling.However,how TCR signals are terminated or attenuated in the distal TCR pathways is largely unknown.We investigated the function of Ser/Thr protein phosphatase 6(PP6) in TCR signaling.T cell lineage-specific ablation of PP6 in mice resulted in enhanced thymic positive and negative selection and preferential expansion of fetal-derived IL-17-producing Vγ6Vδ1~+ T cells.Both PP6-deficient peripheral CD4~+ helper and CD8~+ cytolytic cells could not maintain a naive state and became fast-proliferating and short-lived effector cells.PP6-deficiency led to profound hyperactivation of multiple distal TCR signaling molecules,including MAPKs,AKT and NF-κB.Our studies demonstrate that PP6 acts as a critical negative regulator,not only controlling both αβ and γδlineage development but also maintaining na(i|¨)ve T cell homeostasis by preventing their premature activation prior to antigen stimulation.更多还原