组织原位记忆T细胞(Tissue-resident memory T cell, Trm)是新发现记忆T细胞亚群，除提供保护性免疫外，还介导自身免疫性疾病，但是否参与狼疮肾炎(LN)未有报道。本项目在预实验发现狼疮小鼠肾脏有大量Trm及Trm细胞内钙离子浓度显著升高基础上，提出Trm参与LN进展的假说。本项目分析人LN和自发狼疮小鼠肾脏Trm数目和功能及其与蛋白尿、肾功能和组织学损害的关系；用单克隆抗体清除Trm和基因敲除小鼠，证明Trm参与LN发病机制；构建LN肾移植模型做进一步验证。用化学抑制剂体内干预，研究CD38和STIM1-Orai1介导内质网钙池操控钙内流(SOCE)而调控Trm分化与功能，参与LN发病和进展；体外诱导人和小鼠Trm分化，研究SOCE信号是如何调控Trm分化和功能。本项目将阐明Trm在LN中的作用及调控因素，为提高LN缓解、减少复发提出新思路。

Tissue-resident memory T cell (Trm) is a newly discovered memory T cell subset. In addition to its immune protective function, Trm may also mediate autoimmune diseases. Whether Trm is involved in the pathogenesis of lupus nephritis (LN) is not known. Based on our preliminary findings of presence of large numbers of Trm cells in the kidneys of LN and increased intracellular calcium level in Trm, we propose the hypothesis that Trm is involved in the pathogenesis of LN. This project will investigate the number and function of Trm and their correlation with proteinuria, renal function and histology in human LN and in kidneys of lupus-prone mice. Monoclonal antibody or gene knock will be used to eliminate Trm so as to demonstrate the roles of Trm in LN. A LN kidney transplant model will be established for further confirmation. In vivo treatment with chemical inhibitors will be used to confirm that STIM1-Orai1 and CD38-mediated store-operated calcium entry (SOCE) regulates differentiation and function of Trm and participates in development and progression of LN. The results of this project would reveal the roles of Trm in the pathogenesis of LN, thus open a novel avenue for improving remission and reducing flares in LN.