mTOR和TGFβ信号通路调控DETCs诱导T细胞分化在皮肤移植排斥反应中的作用及机理研究

表皮内γδT细胞（DETCs）是皮肤免疫系统中的重要细胞并参与皮肤移植排斥反应。我们前期研究首次发现：①.DETCs具有专职递呈细胞的功能，其激活后自发性高表达IFNγ并诱导Th1细胞产生，过继到受体小鼠能加速排斥反应；②.经雷帕霉素和TGFβ共培养后，DETCs显著下调IFNγ/上调Foxp3和TGFβ的表达并诱导Treg产生，过继到受体小鼠能抑制排斥反应；但雷帕霉素或TGFβ单独培养则无此效应。提示mTOR与TGFβ信号通路在DETCs调节皮肤排斥反应中起重要作用。而FoxO和Smad是调控T细胞分化关键转录因子Foxp3/T-bet产生的重要分子。因此，本课题拟在前期基础上提出并验证假说：mTORC2-Akt-FoxO和TGFβ-smad信号通路通过调控DETCs转录因子T-bet/Foxp3表达来调节细胞因子IFNγ和TGFβ的产生，从而影响T细胞分化方向以调节皮肤移植免疫反应。

The traditional view of skin transplantation is that langerhan cells (LC) is critical for skin allograft rejection, because it carry allograft antigen to activate recipient na?ve T cells in peripheral lymph nodes. However, current data demonstrated that only LCs were not enough to cause allograft skin rejection. Dendritic epidermal T cells (DETCs) are T lymphocytes that express a canonical TCR γδ and form a dense network in skin. Our preliminary datas showed that activated DETCs refractorily produced high level of IFNγ and could directly induce naive CD4 T cells to differentiate to Th1 cells and promote skin allograft rejection.However, treated with rapamycin and TGFβ, DETCs significantly down-regulated expression of IFN gamma and up-regulated expression of Foxp3 and TGFβ, and induced na?ve CD4 T cells to differentiate to Treg cells and inhibited skin allograft rejection.Accordingly, we here will provide and testify the hypothesis: Both mTORC2-Akt-FoxO and TGFβ-smad signal transduction pathway regulate expression of the key transcription factors T-bet and Foxp3; T-bet promotes production of IFN gamms, wheras, Foxp3 enhances the expression of TGFβ; Then, IFNgamma+ DETCs induced na?ve T cells to differentiate to Th1 cells, which promote allograft rejection; TGFbeta+ DETCs induced na?ve T cells to differentiate to Treg cells, which inhibit allograt rejection.