间充质干细胞通过CD73/CD39/腺苷-PI3K/Akt-Nrf2信号轴调节CD4+IL-10+IFN-γ+T细胞分化减弱GVHD机制研究

T细胞活化与氧化还原代谢紊乱所引发的T细胞亚群失衡是移植物抗宿主病（GVHD）产生的主要原因。我们发现人胎盘间充质干细胞（hPMSCs）可调节CD4+T细胞氧化代谢，促进CD4+IL-10+IFN-γ+T细胞分化减弱GVHD，但机制不清。项目拟构建人源化GVHD模型并结合临床资料，研究hPMSCs通过CD73/CD39/腺苷通路激活CD4+T细胞腺苷受体（ARs），影响胞内PI3K/Akt-Nrf2信号轴活化，上调Nrf2通路及其下游抗氧化基因表达，促进CD4+IL-10+IFN-γ+T细胞分化，减弱GVHD炎症反应的相关分子机制。研究结果将揭示hPMSCs诱导CD4+IL-10+IFN-γ+T细胞形成的分子机制，明确hPMSCs对不同GVHD靶器官中该T细胞亚群产生的调节特点，找到解决由T细胞活化与氧化还原代谢紊乱所致的T细胞亚群失衡问题的有效方法，为治疗GVHD提供实验依据。

The imbalance of T cell subsets caused by the T cell activation and disorder of redox metabolism is the main reason for graft versus host disease (GVHD). We have found that human placenta derived mesenchymal stem cells (hPMSCs) can regulate the oxidative metabolism of CD4+T cells, promote the differentiation of CD4+IL-10+IFN-γ+T cells and weaken GVHD, but the mechanism is unclear. In this study, we will establish humanized GVHD model combined with clinical data to elucidate the molecular mechanism of hPMSCs activating CD4+T cell adenosine receptors (ARs) through CD73/CD39/adenosine pathway, affecting the activation of intracellular PI3K/Akt-Nrf2 signal axis, up regulating Nrf2 pathway and its downstream antioxidant gene expression, promoting CD4+IL-10+IFN-γ+T cell differentiation and weakening GVHD. The expected results will elucidate the molecular mechanism of hPMSCs induced CD4+IL-10+IFN-γ+T cells formation, clarify the regulatory characteristics of hPMSCs on the generation of CD4+IL-10+IFN-γ+T cell subsets in different GVHD target organs, find an effective way to solve the imbalance of T cell subsets caused by the disorder of T cell activation and redox metabolism, and provide experimental support for the treatment of GVHD.