IL-21-TET2-AIM2通路介导的CD4+Trm细胞异常分化及其在系统性红斑狼 疮发生发展中的作用及机制研究

T细胞异常分化、活化在系统性红斑狼疮(SLE)发生发展中起重要作用。循环中T细胞的异常不能完全解释SLE的迁延不愈与复发。组织原位记忆型(Trm)细胞是新发现的T细胞亚型，参与原位炎症及自身免疫反应。我们前期工作发现CD4+Trm细胞在SLE患者皮损及肾脏组织中异常增多；运用单细胞测序及多光谱病理成像发现SLE皮损中高表达CD4+Trm细胞、AIM2、TET2及IL-21；AIM2在滤泡性辅助T细胞(Tfh)中受到IL-21-TET2调控。国际上关于CD4+Trm细胞在SLE中的表达及功能、AIM2在T细胞中表达及功能的研究仍处于空白。该项目拟运用体内外基因敲除体系、焦磷酸盐测序、染色质免疫共沉淀及活体成像等技术探明IL-21-TET2-AIM2通路对CD4+Trm细胞的调控机制，揭示SLE复发的分子机理。该研究将揭示AIM2在Trm细胞中的全新作用机制，为SLE的治疗提供潜在靶点。

Increasing evidence has shown a key role of abnormally differentiated T cells in the pathogenesis of systemic lupus erythematosus (SLE). However, these circulating abnormal T cells can not completely explain the relapse of lupus. Tissue resident memory T (Trm) cells are a newly identified T cell subtype, and they are involved in the in situ inflammation and autoimmune responses. In our previous study, we found increased frequency of CD4+ Trm cells in SLE skin lesion and kidney biopsy. These CD4+ Trm cells from skin lesion were further sorted and sequenced by single cell sequencing technique. AIM2 was found to be highly expressed by these CD4+ Trm cells, as well as TET2 and IL-21. In addition, AIM2 has been found to be regulated by IL-21-TET2 in Tfh cells. The expression and function of Trm cells in lupus and the role of AIM2 in Trm cell differentiation have not been reported. This study aims to apply in vitro and in vivo gene knock-down system, BSP, chromatin immunoprecipitation-sequencing, and in vivo image to explore the regulation from IL-21-TET2-AIM2 pathway in CD4+ Trm cell differentiation, and reveal the molecular mechanisms for lupus relapse. This study will reveal a brand new mechanism for AIM2 regulating Trm cell differentiation, and provide effective therapeutic targets for SLE treatment.