类风湿关节炎（RA）是慢性炎症性自身免疫性疾病，效应性CD4+T细胞亚群分化失衡与记忆性T细胞持续存在导致免疫紊乱是疾病机制的关键。我们已有研究发现锌指蛋白PLZF可调控胸腺细胞诱导的T细胞发育。项目前期发现RA患者外周血CD4+T细胞中锌指蛋白PLZF表达显著升高，STAT3活化增强，且其Th17细胞分化增强、Treg分化抑制和记忆性T细胞生成增加；阻断PLZF可抑制STAT3活化，干预上述分化特征。我们聚焦的科学问题是RA中锌指蛋白PLZF调控效应性T细胞亚群失衡及记忆性T细胞生成的致病机制。项目拟系统研究和明晰锌指蛋白PLZF对RA免疫紊乱的影响；解析PLZF上调可维持STAT3信号通路持续活化，介导效应性T细胞Th17/Treg亚群分化失衡，抑制效应性T细胞凋亡并促进其转变为记忆性T细胞且长期维持，导致RA疾病持续的机制；揭示其重要调控分子，为形成RA诊疗新策略提供理论和实验依据。

Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease. The immune disorder caused by the imbalance of differentiation of effector CD4+T cell subsets and the persistence of memory T cells is the key mechanism of RA. We have found that the zinc finger protein PLZF regulates thymocyte-induced CD4+T cell differentiation. The preliminary study of this project found that PLZF expression was significantly increased in peripheral CD4+T cells of RA patients, with enhanced activation of STAT3, promotion of Th17 cell differentiation and decrease of regulatory T cell (Treg) production. Blocking of PLZF inhibited STAT3 activation and reversed the differentiation state of CD4+T cells of RA patients. Our project mainly focused on the pathological mechanism of zinc finger protein PLZF regulating the imbalance of effector T cell subset differentiation and memory T cell production. This project intends to systematically study and clarify the effect of PLZF on immune disorders in RA; reveal the cellular and molecular mechanism of PLZF upregulating and maintaining activation of STAT3 signaling pathway, mediating the imbalance of Th17/Treg cell subsets in effector T cells, and inhibiting effector T cell apoptosis, promoting it to transform into memory T cells and long-term maintenance, leading to RA; reveal important regulatory molecules to provide theoretical and experimental basis for exploring the formation of new strategies for RA diagnosis and treatment.