| First Author | Bhaumik S | Year | 2021 |
| Journal | J Immunol | Volume | 207 |
| Issue | 8 | Pages | 2027-2038 |
| PubMed ID | 34518282 | Mgi Jnum | J:331158 |
| Mgi Id | MGI:6849678 | Doi | 10.4049/jimmunol.2100175 |
| Citation | Bhaumik S, et al. (2021) RORgammat Promotes Foxp3 Expression by Antagonizing the Effector Program in Colonic Regulatory T Cells. J Immunol 207(8):2027-2038 |
| abstractText | RORgammat is the master transcription factor for the Th17 cells. Paradoxically, in the intestine, RORgammat is coexpressed in peripherally induced regulatory T cells (pTregs) together with Foxp3, the master transcription factor for Tregs. Unexpectedly, by an unknown mechanism, colonic RORgammat(+) Tregs show an enhanced suppressor function and prevent intestinal inflammation more efficiently than RORgammat-nonexpressing pTregs. Although studies have elucidated the function of RORgammat in Th17 cells, how RORgammat regulates pTreg function is not understood. In our attempt to understand the role of RORgammat in controlling Treg function, we discovered a RORgammat-driven pathway that modulates the regulatory (suppressor) function of colonic Tregs. We found that RORgammat plays an essential role in maintaining Foxp3 expression. RORgammat-deficient Tregs failed to sustain Foxp3 expression with concomitant upregulation of T-bet and IFN-gamma expressions. During colitis induced by adoptive transfer of CD45RB(hi) cells in Rag1 (-/-) mice, RORgammat-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, RORgammat-deficient Tregs showed impaired therapeutic efficacy in ameliorating colitis that is not due to their reduced survival. Moreover, using the Treg-specific RORgammat and T-bet double-deficient gene knockout mouse, we demonstrate that deletion of T-bet from RORgammat-deficient Tregs restored Foxp3 expression and suppression function as well as prevented onset of severe colitis. Mechanistically, our study suggests that RORgammat-mediated repression of T-bet is critical to regulating the immunosuppressive function of colonic Tregs during the inflammatory condition. |
