RORγt is the master transcription factor for the Th17 cells. Paradoxically, in the intestine, RORγt is coexpressed in peripherally induced regulatory T cells (pTregs) together with Foxp3, the master transcription factor for Tregs. Unexpectedly, by an unknown mechanism, colonic RORγt⁺ Tregs show an enhanced suppressor function and prevent intestinal inflammation more efficiently than RORγt-nonexpressing pTregs. Although studies have elucidated the function of RORγt in Th17 cells, how RORγt regulates pTreg function is not understood. In our attempt to understand the role of RORγt in controlling Treg function, we discovered a RORγt-driven pathway that modulates the regulatory (suppressor) function of colonic Tregs. We found that RORγt plays an essential role in maintaining Foxp3 expression. RORγt-deficient Tregs failed to sustain Foxp3 expression with concomitant upregulation of T-bet and IFN-γ expressions. During colitis induced by adoptive transfer of CD45RB^hi cells in Rag1^−/− mice, RORγt-deficient colonic Tregs transitioned to a Th1-like effector phenotype and lost their suppressor function, leading to severe colitis with significant mortality. Accordingly, Foxp3-expressing, RORγt-deficient Tregs showed impaired therapeutic efficacy in ameliorating colitis that is not due to their reduced survival. Moreover, using the Treg-specific RORγt and T-bet double-deficient gene knockout mouse, we demonstrate that deletion of T-bet from RORγt-deficient Tregs restored Foxp3 expression and suppression function as well as prevented onset of severe colitis. Mechanistically, our study suggests that RORγt-mediated repression of T-bet is critical to regulating the immunosuppressive function of colonic Tregs during the inflammatory condition.

RORγt 是 Th17 细胞的主要转录因子。矛盾的是，在肠道中，RORγt 在外周诱导的调节性 T 细胞 (pTregs) 中与 Foxp3（Treg 的主要转录因子）共表达。出乎意料的是，通过未知机制，结肠 RORγt ⁺Treg 显示出增强的抑制功能，并且比不表达 RORγt 的 pTreg 更有效地预防肠道炎症。尽管研究阐明了 RORγt 在 Th17 细胞中的功能，但尚不清楚 RORγt 如何调节 pTreg 功能。在我们试图了解 RORγt 在控制 Treg 功能中的作用时，我们发现了一个 RORγt 驱动的途径，可以调节结肠 Treg 的调节（抑制）功能。我们发现 RORγt 在维持 Foxp3 表达中起着至关重要的作用。RORγt 缺陷型 Treg 无法维持 Foxp3 表达，同时 T-bet 和 IFN-γ 表达上调。在Rag1 中过继转移 CD45RB ^hi细胞诱导结肠炎期间^-/-在小鼠中，RORγt 缺陷的结肠 Treg 转变为 Th1 样效应器表型并失去抑制功能，导致严重的结肠炎，死亡率很高。因此，表达 Foxp3、RORγt 缺陷的 Tregs 在改善结肠炎方面表现出受损的治疗效果，这不是由于它们的存活率降低。此外，使用 Treg 特异性 RORγt 和 T-bet 双缺陷基因敲除小鼠，我们证明从 RORγt 缺陷 Treg 中删除 T-bet 恢复了 Foxp3 表达和抑制功能，并防止了严重结肠炎的发作。从机制上讲，我们的研究表明，RORγt 介导的 T-bet 抑制对于调节炎症期间结肠 Treg 的免疫抑制功能至关重要。