阻断PD-1/PD-L1信号调控CD8+Trm细胞异常活化诱导1型糖尿病的发生与机制

1型糖尿病（T1DM）是一种T细胞介导的器官特异性自身免疫性疾病，申请人首先发现在1型糖尿病模型小鼠胰岛组织中有CD8+组织驻留记忆T细胞（CD8+Trm）的浸润，阻断PD-1信号后会导致CD8+Trm异常活化。由此提出：阻断PD1/PD-L1信号激活了胰岛局部微环境的CD8+Trm，损伤胰岛β细胞，导致T1DM的发生。本项目将使用动物模型、胰岛组织标本和细胞系，采用单细胞测序技术、分子生物学方法等手段，动态观察CD8+Trm在T1DM疾病进展中的表达及生物学功能变化，探讨PD-1/PD-L1信号调控CD8+Trm细胞参与T1DM发病的临床意义，探索PD-L1融合蛋白延缓T1DM发病的可行性。本研究将通过探索PD-1/PD-L1调控CD8+Trm 诱导（延缓）1型糖尿病的机制，为1型糖尿病的免疫机制研究提供更丰富的信息，并为1型糖尿病的干预提供新的靶点和思路。

Type 1 diabetes (T1DM) is an organ-specific autoimmune disease mediated by T cells. Cytotoxic CD8+T cells were previously thought to be the dominating cells attacking β cell. Recently, we found the infiltration of CD8+ tissue resident memory T cells (CD8+Trm) in the pancreas of NOD mice, and the expression level of PD-1 decreased with the progression of the disease. Therefore, it was proposed that the lack of PD-1/PD-L1 signaling pathway activated CD8+Trm in the microenvironment of the islet, and damaged the β cells, leading to the occurrence of T1DM. This project will dynamically observe the changes and biological characteristics of CD8+Trm by means of cell and molecular biology in animal models, islet tissue and cell lines to investigate the clinical significance of PD-1/ PD-L1 signal in regulating the involvement of CD8+Trm in the pathogenesis of T1DM. This project will provide a new idea for the study of the mechanism of T1DM from the perspective of CD8+Trm, provide a theoretical basis for the PD-1/PD-L1-targeted therapy of T1DM.