PI16通过BMI1介导的组蛋白修饰机制影响Treg细胞稳定性参与类风湿关节炎病理过程的研究

Foxp3+Treg细胞在维持免疫耐受中发挥关键作用。近年发现部分Treg细胞在炎症状态下不稳定，存在丢失Foxp3表达的现象，机制尚不清楚。既往我们通过基因芯片发现类风湿关节炎患者（RA）外周血单个核细胞中肽酶抑制蛋白16（PI16）表达上调。预实验构建PI16转基因鼠并诱导关节炎模型（CIA模型），发现PI16过表达鼠炎症及骨侵蚀加重，同时脾脏T细胞中Foxp3表达减少。通过ChIP-qPCR发现PI16能与表观遗传调节因子BMI1相互作用，并结合到Foxp3启动子。本研究假说：炎症状态下，PI16通过BMI1介导的组蛋白修饰机制抑制Foxp3转录，从而影响Treg细胞的稳定性，参与RA病理过程。将通过构建Treg细胞中PI16定向敲除鼠，明确PI16对CIA炎症状态下Treg细胞稳定性的影响及分子机制，为揭示RA免疫失衡机制提供新视角，为寻找靶向调控Treg稳定性的新治疗提供新探索。

Foxp3+regulatory T cells (Tregs) cells plays a key role in maintaining immune homeostasis. Under inflammation condition, a part of Tregs could lose Foxp3 expression and display the instability phenomenon. The exact mechanism remains unclear. We previously identified the high expression of PI16 in PBMC from Rheumatoid arthritis (RA) patients by microarray analysis. In a PI16 transgenic mouse model of arthritis, we found that inflammation and bone erosion were significantly increased, and Foxp3 expression was significantly decreased accordingly in spleen CD4+ T cells. The interaction between PI16 and BMI1 was found in Foxp3 promoter region by ChIP-qPCR. We hypothesized highly expressed PI16 induced by inflammation could inhibit Foxp3 transcription by promoting BMI1 mediated histone modification in Foxp3 promoter participating in the pathological process of RA. Here, using a Treg-specific PI16-deficient mouse constructed by dual-fluorescence reporter, we will study the influence of PI16 on the stability of Treg cells and explore its molecular mechanism in the autoimmune arthritis model. This study aims to provide a new perspective for elucidation of the immune imbalance mechanism of RA, and a new exploration for new treatment for RA and other autoimmune diseases by targeting the stability of Treg cells.