T cell development proceeds un der the in fluence of a n etwork of transcription factors(TFs).The precise role of Zeb1,a member of this network,remains unclear.Here,we report that Zeb1 expression is induced early duri...T cell development proceeds un der the in fluence of a n etwork of transcription factors(TFs).The precise role of Zeb1,a member of this network,remains unclear.Here,we report that Zeb1 expression is induced early during T cell development in CD4^(-)CD8^(-)double-negative(DN)stage 2(DN2).Zeb1 expression was further increased in the CD4^(+)CD8^(+)double-positive(DP)stage before decreasing in more mature T cell subsets.We performed an exhaustive characterization of T cells in Cellophane mice that bear Zeb 7 hypomorphic mutations.The Zebl mutation profoundly affected all thymic subsets,especially DN2 and DP cells.Zeb1 promoted the survival and proliferation of both cell populations in a cell-intrinsic manner.In the periphery of Cellophane mice,the number of conventional T cells was near normal,but invariant NKT cells,NK1.1^(+)γδ T cells and Ly49^(+)CD8 T cells were virtually absent.This suggested that Zebl regulates the development of unconventional T cell types from DP progenitors.A transcriptomic analysis of WT and Cellophane DP cells revealed that Zebl regulated the expression of multiple genes involved in the cell cycle and TCR sign aling,which possibly occurred in cooperation with Tcf1 and Heb.In deed,Cellophane DP cells displayed stron ger signaling than WT DP cells upon TCR engagement in terms of the calcium respons巳phosphorylation events,and expression of early genes.Thus,Zebl is a key regulator of the cell cycle and TCR signaling during thymic T cell development.We propose that thymocyte selection is perturbed in Zeb7-mutated mice in a way that does not allow the survival of unconventional T cell subsets.展开更多
基金The TW lab is supported by the Agence Nationale de la Recherche(ANR GAMBLER to TW and ANR JC BaNK to AM)the Institut National du Cancer and receives institutional grants from the Institut National de la Sante et de la Recherche Medicale(INSERM)+4 种基金Centre National de la Recherche Scientifique(CNRS)Universite Claude Bernard Lyon and ENS de Lyonthe Joint Research Institute for Science and Society(JORISS)JZ is the recipient of a fellowship from the China Scholarship Council(CSC)RS and YGH were funded by an FRM grant(AJE20161236686)to YGH.
文摘T cell development proceeds un der the in fluence of a n etwork of transcription factors(TFs).The precise role of Zeb1,a member of this network,remains unclear.Here,we report that Zeb1 expression is induced early during T cell development in CD4^(-)CD8^(-)double-negative(DN)stage 2(DN2).Zeb1 expression was further increased in the CD4^(+)CD8^(+)double-positive(DP)stage before decreasing in more mature T cell subsets.We performed an exhaustive characterization of T cells in Cellophane mice that bear Zeb 7 hypomorphic mutations.The Zebl mutation profoundly affected all thymic subsets,especially DN2 and DP cells.Zeb1 promoted the survival and proliferation of both cell populations in a cell-intrinsic manner.In the periphery of Cellophane mice,the number of conventional T cells was near normal,but invariant NKT cells,NK1.1^(+)γδ T cells and Ly49^(+)CD8 T cells were virtually absent.This suggested that Zebl regulates the development of unconventional T cell types from DP progenitors.A transcriptomic analysis of WT and Cellophane DP cells revealed that Zebl regulated the expression of multiple genes involved in the cell cycle and TCR sign aling,which possibly occurred in cooperation with Tcf1 and Heb.In deed,Cellophane DP cells displayed stron ger signaling than WT DP cells upon TCR engagement in terms of the calcium respons巳phosphorylation events,and expression of early genes.Thus,Zebl is a key regulator of the cell cycle and TCR signaling during thymic T cell development.We propose that thymocyte selection is perturbed in Zeb7-mutated mice in a way that does not allow the survival of unconventional T cell subsets.
