RORγt调控肠黏膜组织中Th17细胞表达IL-10参与肠道炎症发生的机制研究

T helper 17 (Th17) cell is essential to the pathogenesis of inflammatory bowel disease (IBD) and shows a substantial degree of plasticity in response to environmental cues. Th17 cells have been well-established in mediating the pathogenesis of IBD, but it is equally clear that these cells also have a critical protective role in the defence against opportunistic pathogens of fungal or bacterial origin. Retinoid-related orphan receptor gamma t (RORγt) has been identified the master transcription factor of Th17. The role of RORγt in driving Th17 cell differentiation has been well-established, however, how it regulates pathogenicity of Th17 cells in autoimmune diseases is still not completely understood. We report here that the specific RORt inhibitor ameliorates CBir1 T induced colitis of mice. Treatment with a specific RORt inhibitor suppressed Th17 cell signature cytokines, but promoted IL-10 production. These data indicate that while promoting Th17 cell differentiation, RORγt inhibited IL-10 production by T cells, thereby preserving the pathogenicity of Th17 cells. In this study, we will investigate the role of RORγt inhibitor-treated Th17 cells in regulation of CD4+ T cells proliferation and T cell induced colitis and the mechanism of IL-10 production. This work will determine the regulatory role of RORγt inhibitor in colitis, and provide an important therapeutic target for human IBD.

Th17细胞在炎症性肠病（IBD）发病中具有重要作用，在肠道炎症免疫调节中，Th17细胞既能促进炎症的进展，加重自身免疫反应，也能抵御细菌及真菌入侵，对肠黏膜起到保护性作用。RORγt是促进Th17分化的重要转录因子，但在IBD发病中RORγt如何调节Th17致病性仍未研究清楚。我们前期研究发现，RORγt抑制剂能阻止CBir1 T细胞诱导的小鼠慢性结肠炎发生，有效抑制肠黏膜组织内Th17特征性细胞因子IL-17表达，促进IL-10产生，表明RORγt在促进Th17分化的同时，抑制了IL-10表达，维持了Th17的致病性。本课题利用体外T细胞共培养以及Th17诱导的小鼠结肠炎模型，重点研究RORγt抑制剂作用后的Th17如何调节CD4+ T细胞增殖及结肠炎症的发生，以及RORγt调节Th17产生IL-10的具体机制。阐明RORγt抑制剂缓解肠道炎症的免疫调节机制，为IBD治疗提供新的思路。

Th17 细胞在炎症性肠病（IBD）发病中具有重要作用，在肠道炎症免疫调节中，Th17 细胞既能促进炎症的进展，加重自身免疫反应，也能抵御细菌及真菌入侵，对肠黏膜起到保护性作用。RORγt 是促进Th17分化的重要转录因子，但在IBD发病中RORγt 如何调节Th17 致病性仍未研究清楚。本课题体在外诱导Th17 细胞时，给予RORγt抑制剂（RORγti）处理，发现IL-17、IL-22 等细胞因子表达下降，而IL-10 表达明显升高。而将RORγti 处理过的Th17（RORγti- Th17）与CD4+T 细胞共培养后，发现RORγti- Th17 可以明显抑制CD4+T 的增殖，但是用抗-IL-10 抗体阻断后，这种抑制作用消失。并且RORγti- Th17 诱导的小鼠结肠炎相对于Th17 诱导的小鼠结肠炎，肠道炎症有所减轻。最终，我们研究发现，RORγt 通过抑制Th17 细胞blimp1 表达，进而抑制Il-10 表达。RORγti 能阻止CBir1 T 细胞诱导的小鼠慢性结肠炎发生，有效抑制肠黏膜组织内Th17 特征性细胞因子IL-17 表达，通过诱导blimp1 表达，促进IL-10 产生，表明RORγt 在促进Th17 分化的同时，抑制了IL-10 表达，维持了Th17 的致病性。本课题通过阐明RORγti 缓解肠道炎症的免疫调节机制，为IBD治疗提供新的思路。