RORgt promotes Foxp3 expression by antagonizing the effector program in colonic regulatory T cells

Academic Article

Abstract

  • RORgt is the master transcription factor for the Th17 cells. Paradoxically, in the intestine, RORgt is coexpressed in peripherally induced regulatory T cells (pTregs) together with Foxp3, the master transcription factor for Tregs. Unexpectedly, by an unknown mechanism, colonic RORgt+ Tregs show an enhanced suppressor function and prevent intestinal inflammation more efficiently than RORgt-nonexpressing pTregs. Although studies have elucidated the function of RORgt in Th17 cells, how RORgt regulates pTreg function is not understood. In our attempt to understand the role of RORgt in controlling Treg function, we discovered a RORgt-driven pathway that modulates the regulatory (suppressor) function of colonic Tregs. We found that RORgt plays an essential role in maintaining Foxp3 expression. RORgt-deficient Tregs failed to sustain Foxp3 expression with concomitant upregulation of T-bet and IFN-g expressions. During colitis induced by adoptive transfer of CD45RBhi cells in Rag12/2 mice, RORgt-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, RORgt-deficient Tregs showed impaired therapeutic efficacy in ameliorating colitis that is not due to their reduced survival. Moreover, using the Treg-specific RORgt and T-bet double-deficient gene knockout mouse, we demonstrate that deletion of T-bet from RORgt-deficient Tregs restored Foxp3 expression and suppression function as well as prevented onset of severe colitis. Mechanistically, our study suggests that RORgt-mediated repression of T-bet is critical to regulating the immunosuppressive function of colonic Tregs during the inflammatory condition.
  • Authors

    Published In

    Digital Object Identifier (doi)

    Author List

  • Bhaumik S; Mickael ME; Moran M; Spell M; Basu R
  • Start Page

  • 2027
  • End Page

  • 2038
  • Volume

  • 207
  • Issue

  • 8