PD-1通路和Treg细胞在维持免疫耐受方面起着重要作用。Treg细胞组成性表达PD-1分子，但PD-1对Treg细胞功能的影响依然存在争议。在前期工作中，我们鉴定了催化PD-1泛素化修饰的关键E3连接酶FBXO38（Nature 2018，第一作者），进一步研究发现FBXO38可以通过Treg细胞影响肠道免疫稳态。本项目将以肠炎为模型，研究PD-1泛素化修饰对Treg细胞功能的影响。我们将首先研究Treg细胞中PD-1的表达动态和泛素化修饰类型，以及PD-1对Treg细胞免疫抑制功能的影响；随后利用Fbxo38敲除小鼠研究PD-1泛素化修饰对Treg细胞维持肠道免疫稳态的影响；最后将着重研究Fbxo38在肠道Treg细胞中的表达调控机制，揭示其与肠炎发生发展的关系。本项目的实施将从PD-1稳定性角度揭示PD-1通路对Treg细胞功能的影响，并提供新的肠炎发生机制。

PD-1 pathway and Treg cell play important roles in maintaining immune tolerance. Treg cells constitutively express PD-1 molecule, but the effect PD-1 pathway on Treg cell function remains controversial. In the previous work, we identified the key E3 ligase FBXO38 that catalyzes PD-1 ubiquitination modification (Nature 2018, first author), and further research found that FBXO38 can regulate intestinal immune homeostasis through Treg cells. Here we use murine colitis model to study the effects of PD-1 ubiquitination modification on Treg cell function. We will first study PD-1 expression dynamics and the type of ubiquitination type, along with the effects of PD-1 signaling for Treg cell function; then through Fbxo38 conditional knockout mice, we aim to study the effects of PD-1 ubiquitination modification on the maintenance of intestinal immune homeostasis induced by Treg cells. Finally, the expression regulation mechanism of Fbxo38 in intestinal Treg cells will be studied, and its relationship with the development of colitis will be revealed. The implementation of this project will reveal the effects of PD-1 ubiquitination modification on Treg cell function and provide a new mechanism of colitis.