ROR γt Promotes Foxp3 Expression by Antagonizing the Effector Program in Colonic Regulatory T Cells

J Immunol. 2021 Sep 13:ji2100175. doi: 10.4049/jimmunol.2100175. Online ahead of print.ABSTRACTRORγt 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 CD45RBhi 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...
Source: Journal of Immunology - Category: Allergy & Immunology Authors: Source Type: research