TCR/NKG2D共刺激诱导CD4+NKG2D+T细胞表达TGF-β的转录调控机制

项目名称： TCR/NKG2D共刺激诱导CD4+NKG2D+T细胞表达TGF-β的转录调控机制

项目编号： No.81471547

项目类型： 面上项目

立项/批准年度： 2015

项目学科： 医药、卫生

项目作者： 龚卫娟

作者单位： 扬州大学

项目金额： 75万元

中文摘要： 我们前期工作发现，荷瘤小鼠及pCD86-RAE-1转基因小鼠体内存在一群独特的调节性CD4+NKG2D+T细胞，受TCR和NKG2D的共同刺激而活化，表达膜型TGF-β和FasL发挥免疫调节作用。然而关于TCR/NKG2D活化后诱导TGF-β转录的分子机制，目前尚不清楚。本研究拟首先观察受TCR/NKG2D共刺激后，该调节性CD4+NKG2D+T细胞内NF-κB的活化情况及其是否调控TGF-β基因的转录，而去磷酸化STAT3是否通过与NF-κB的结合间接调控TGF-β基因的转录；其次分析Egr3是否及如何调控TGF-β基因的转录；并且观察由MAPK/PI3K途径介导的AP-1活化在TGF-β基因转录调控中的作用。研究结果将阐明CD4+NKG2D+T细胞内由TCR/NKG2D受体介导的TGF-β转录调控机制，为基于抑制CD4+NKG2D+T细胞的生物学活性来开发新型抗肿瘤药物提供实验依据。

中文关键词： 调节性T细胞；NKG2D；TGF-β；转录调控；核转录因子

英文摘要： There are unconventional CD4+NKG2D+T cells with regulatory function in the tumor-bearing mice and the pCD86-RAE-1 transgenic mice, which were identified by our previous research work. With co-ligations of TCR and NKG2D, CD4+NKG2D+T cells are activated to mediate regulatory activity through expression of membrane-bound TGF-β and FasL. However, the molecular mechanisms of TGF-β transcription induced by co-activations of TCR and NKG2D remain unknown. Whether NF-κB could be activated and how activated NF-κB regulates TGF-β transcription in CD4+NKG2D+T cells will be observed firstly in this study. Whether dephosphorylated STAT3 indirectly regulates TGF-β transcription by binding to NF-κB will be also investigated. Next we will analyze whether and how Egr-3 transactivates TGF-β transcription in CD4+NKG2D+T cells. In addition, how nuclear factor AP-1 which is activated by the MAPK/PI3K signaling pathway functions to regulate TGF-β transcription will be investigated. Therefore the mechanisms of TGF-β transcriptional regulation in CD4+NKG2D+T cells induced by co-stimulations of TCR and NKG2D will be finally elucidated.This study will also provide experimental evidences?for development of new anti-tumor drugs based on inhibition of biological activities of CD4+NKG2D+T cells.

英文关键词： Regulatory T cells;NKG2D;TGF-β;transcriptional regulation;nuclear factor