去泛素化酶POH1调控CD4+Foxp3+调节性T细胞分化和维持的机制研究

CD4+Foxp3+ Regulatory T (Treg) cells play a critical role in the maintenance of self-tolerance and control of inflammatory responses. Deubiquitination is a protein post-translational modification, which controls a lot of critical cellular events. However, whether deubiquitinating enzyme is involved in the regulation of CD4+Foxp3+ Treg cell differentiation and maintenance is incompletely understood. Our preliminary data have shown that the frequency of thymic CD4+Foxp3+ Treg cells is dramatically decreased in mice with T cell-specific deficiency in POH1, partly because of the impaired differentiation of Treg progenitor cells and decreased proliferation of CD4+Foxp3+ Treg cells. In the present study, we will investigate the effect of POH1 on the regulation of Treg cell development mainly including the following three aspects: 1. The effect of POH1 on the generation and maintenance of thymic Treg cell. 2. The distinct role of POH1 in the different stage of thymic Treg cell development. 3. The mechanism underlying the POH1-mediated modulation of thymic Treg cell differentiation and maintenance. The study will improve our understanding of how POH1 modulates the development and maintenance of Treg cell in the thymus.

CD4+Foxp3+调节性T（Treg）细胞在维持自身免疫耐受和控制炎症中发挥关键作用。去泛素化是重要的蛋白修饰方式，但关于去泛素化事件在CD4+Foxp3+Treg细胞分化和维持中的作用还不清楚。我们预实验结果表明，T细胞中去泛素化酶POH1的缺失，导致胸腺CD4+Foxp3+Treg细胞比例明显下降，其原因可能与胸腺Treg前体细胞分化能力下降及CD4+Foxp3+Treg细胞增殖能力受损有关。本课题将利用T细胞或Foxp3+细胞敲除POH1的小鼠模型，聚焦研究POH1在CD4+Foxp3+Treg细胞分化发育和生成后维持的调控作用：1.分析POH1缺失对Treg细胞产生和生成后维持的影响；2.确定POH1在Treg细胞分化发育各个阶段的不同调控作用；3.阐明POH1调控Treg细胞分化和生成后维持的分子机制。该研究将为认识POH1在Treg细胞发育和维持过程中的调控作用提供理论依据。

表达Foxp3的调节性T(Treg)细胞在防止自身免疫性疾病和维持免疫稳态中发挥非常重要的作用。但是，Treg细胞分化发育和维持的分子机制仍然不是很清楚。我们的研究发现，T细胞特异性敲除去泛素化酶POH1抑制成熟T细胞的发育，特别是CD4+Foxp3+Treg细胞。并且，POH1缺失降低IL-2-STAT5信号通路的激活，使胸腺CD25+Treg前体细胞向Foxp3+Treg 细胞转化能力下降。在CD4+Foxp3+Treg 细胞中特异性地敲除POH1后，小鼠会自发产生致死性的炎症，并且外周Treg细胞群由于其增殖能力降低，比率和数目明显下降。我们的结果表明，POH1在CD4+Foxp3+Treg 细胞的发育、维持以及免疫耐受中发挥着非常重要的作用。