转录共激活因子TAZ在CD4+Treg细胞中的功能与作用研究

The regulatory T cells are an important subpopulation of T cells which suppress the immune system. The disorder of Treg cells will lead to the occurrence of autoimmune diseases. At present the molecular mechanism of Treg cells differentiation has not been fully elucidated. Our previous studies have shown that the deletion of Mst1 in vivo, the core kinase of Hippo pathway, can lead to severe autoimmune diseases. Our unpublished data further show that in the process of CD4+ Naive T cells differentiating into Treg cells, the expression of the Hippo pathway downstream transcriptional co-activator TAZ increased significantly. TAZ deficiency resulted in the differentiation defect of Treg cells and increased the protein levels of Foxp3, a master regulator of Treg cells. Therefore, we hypothesized that TAZ may play a very important role in the regulation of the development and function of Treg cells. In this study, we aim to confirm the regulatory function of TAZ and its molecular mechanism in Treg differentiation. We will analysis samples of the patients with autoimmune diseases and our well-established animal disease models to clarify the function of TAZ in Treg differentiation. The study of this project will provide a new strategy for the mechanism of the occurrence of autoimmune diseases.

调节性T细胞Treg是具有免疫抑制功能的重要细胞类群，该类细胞失调将导致自身免疫疾病的发生。目前Treg细胞分化的分子机制尚未完全阐明。我们前期研究表明Hippo信号通路的重要激酶Mst1缺失后会导致严重的自身免疫疾病。我们未发表数据进一步显示在初始 T细胞分化为Treg细胞过程中，Hippo通路的下游转录共激活因子TAZ的表达显著增加。在T细胞中敲除TAZ后Treg细胞分化受到影响，调控Treg细胞发育的关键转录因子Foxp3的蛋白水平显著上升。因此，我们推测TAZ在调控Treg细胞的发育和功能中可能起十分重要的作用。本项目拟在分子和细胞水平阐明TAZ在Treg细胞的分化过程中的调节功能和分子机理，并通过小鼠疾病模型进行体内验证，进一步探究TAZ与人的自身免疫疾病发生发展的相关性与功能作用。本项目的研究将为自身免疫疾病的发生机制提供理论依据和相关疾病诊疗提供新策略。

调节性T细胞是具有免疫抑制功能的重要细胞类群，该类细胞失调将导致自身免疫疾病的发生。目前Treg细胞分化的分子机制尚未完全阐明。近年来的研究表明Hippo信号通路的重要激酶Mst1缺失后会导致严重的自身免疫疾病。我们实验发现在体外诱导CD4+ Naive T细胞分化成Treg细胞过程Hippo信号通路重要的下游靶点、转录共激活因子TAZ的转录水平和蛋白水平显著上升。在CD4＋ Treg细胞分化过程中，TAZ可以通过降低组蛋白乙酰转移酶Tip60介导的Foxp3的乙酰化作用来促进Foxp3蛋白的降解，进而通过调节Foxp3的稳定性抑制Treg细胞的分化。通过动物模型实验，我们发现TAZ-cKO小鼠对T细胞转移性结肠炎和小鼠自身免疫性脑脊髓炎具有抗性，是由于Treg细胞的诱导和免疫抑制功能增强所致。最后，结合自身性免疫疾病的病人样品分析TAZ与自身免疫疾病存在相关性。本项目通过这一系列实验阐明转录共激活因子TAZ在CD4＋Treg细胞分化过程中的调节作用及其机制，有助于探究自身免疫疾病发病的分子机制，为自身免疫疾病的诊断和治疗提供新策略。