FcμR对炎症性肠病肠黏膜致病性Th17细胞的免疫调控机制研究

Th17细胞包括致病性Th17(pTh17)和非致病性Th17(nTh17)，在炎症性肠病(IBD)发病中发挥重要作用。FcμR是IgM Fc受体蛋白，可影响pTh17和nTh17分化，在IBD中尚无研究。我们前期发现IBD患者肠黏膜FcμR表达上调，外周血CD4+T细胞受IL-12刺激后FcμR表达增高，外周血CD4+T细胞分化为pTh17后FcμR表达较nTh17增高，提示IBD患者FcμR表达异常可能在pTh17/nTh17分化失衡中起关键作用。本课题计划用慢病毒干扰IBD患者CD4+T细胞FcμR表达；利用FcμR-/-小鼠，构建TNBS和CD45RBhiCD25-CD4+T细胞分别诱导的急/慢性结肠炎模型；利用RNA-seq探索FcμR下游信号分子；阐明通过FcμR信号通路调节pTh17/nTh17分化从而改善IBD肠黏膜炎症的免疫机制，为临床免疫治疗IBD提供新靶点。

T helper 17 (Th17) lymphocytes including pathogenic Th17 (pTh17) and non-pathogenic Th17 (nTh17) act as a critical role in the pathogenesis of inflammatory bowel disease (IBD). FcμR, which is a type I transmembrane receptor for IgM Fc, is proved to modulates the differentiation of pTh17 and nTh17 ex vivo. However, the function of FcμR in the pathogenesis of IBD is to be elaborated. Our previous data illustrated that FcμR expression was increased in colonic mucosa from patients with active IBD. Besides, peripheral blood CD4+ T cells isolated from patients with active IBD synthesized more FcμR when stimulated with IL-12, compared with those from healthy donors. Furthermore, FcμR expression was higher in pTh17 cells than nTh17 when peripheral blood CD4+ T cells simulated with IL-6+TGFβ+IL-23 and TGFβ+IL-6 respectively. Hence, we hypothesize that the aberrant FcμR expression in CD4+ T cells potentially results in imbalanced differentiation of pTh17 and nTh17 in intestinal mucosa from patients with IBD. In this study, peripheral blood CD4+ T cells isolated from IBD patients will be transfected with si-FcμR-lentivirus and RNA-seq analysis will be performed to clarify the molecular mechanism of FcμR in regulating pTh17 and nTh17 differentiation. To investigate the role of FcμR in the pathogenesis of IBD, FcμR will be knockout in C57BL/6 mice (FcμR-/-) and TNBS-induced colitis murine model will be applied. pTh17/nTh17 differentiation in intestinal mucosa, MLN, and spleen from mice with colitis will be detected using flow cytometer, qRT-PCR, and western blotting. Furthermore, to investigate whether FcμR mediated signaling pathway in CD4+ T cells contributes to deteriorated inflammation, CD45RBhiCD25-CD4+ T cells will be sorting by flow cytometer from FcμR-/- mice and injected to Rag1-/- mice to induce chronic colitis. Our study will shed light on the immune mechanisms of FcμR mediated signaling pathway in regulation of pTh17 and nTh17 differentiation, which further might provide a new target to treat IBD.