RORγt 抑制 Th17 细胞中 IL-10 的产生以维持其在诱导肠道炎症中的致病性。
RORγt Represses IL-10 Production in Th17 Cells To Maintain Their Pathogenicity in Inducing Intestinal Inflammation.
机构信息
Department of Microbiology and Immunology, The University of Texas Medical Branch, Galveston, TX 77555.
Department of Gastroenterology, The Shanghai Tenth People's Hospital, Tongji University, Shanghai 200072, China.
出版信息
J Immunol. 2019 Jan 1;202(1):79-92. doi: 10.4049/jimmunol.1701697. Epub 2018 Nov 26.
The role of retinoid-related orphan receptor γ t (RORγt) in Th17 cell differentiation has been well established; however, how it regulates other T cell lineages is still not clearly understood. In this study, we report that in mice, while promoting Th17 cell differentiation, RORγt inhibited IL-10 production by T cells, thereby preserving the pathogenicity of Th17 cells. Treatment with RORγ-specific inhibitor suppressed Th17 cell signature cytokines, but promoted IL-10 production. RORγt inhibitor-treated Th17 cells induce less severe colitis compared with control Th17 cells. Mechanistically, the RORγt inhibitor induced T cell expression of Blimp-1 (encoded by Prdm1). Prdm1 T cells produced significantly fewer IL-10 when treated with RORγt inhibitor compared with wild-type T cells. Furthermore, RORγt inhibitor-treated Prdm1 Th17 cells induce more severe colitis compared with RORγt inhibitor-treated wild-type Th17 cells. Collectively, our studies reveal a novel mechanism by which RORγt drives and maintains pathogenic Th17 cell development by inhibiting IL-10 production.
维甲酸相关孤儿受体γ t（RORγt）在 Th17 细胞分化中的作用已得到充分证实；然而，其如何调节其他 T 细胞谱系仍不清楚。在这项研究中，我们报告在小鼠中，RORγt 促进 Th17 细胞分化的同时，抑制 T 细胞产生 IL-10，从而保持 Th17 细胞的致病性。用 RORγ 特异性抑制剂处理会抑制 Th17 细胞特征性细胞因子的产生，但会促进 IL-10 的产生。与对照 Th17 细胞相比，用 RORγ 抑制剂处理的 Th17 细胞诱导的结肠炎较轻。在机制上，RORγ 抑制剂诱导 T 细胞表达 Blimp-1（由 Prdm1 编码）。与野生型 T 细胞相比，用 RORγ 抑制剂处理的 Prdm1 T 细胞产生的 IL-10 明显减少。此外，与用 RORγ 抑制剂处理的野生型 Th17 细胞相比，用 RORγ 抑制剂处理的 Prdm1 Th17 细胞诱导的结肠炎更严重。总之，我们的研究揭示了一种新的机制，即 RORγt 通过抑制 IL-10 的产生来驱动和维持致病性 Th17 细胞的发育。
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