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

Area of Science:

• Immunology
• Molecular Biology
• Gastroenterology

Background:

• RORγt is a key transcription factor for Th17 cells.
• RORγt is paradoxically coexpressed with Foxp3 in intestinal regulatory T cells (Tregs).
• RORγt+ Tregs exhibit enhanced suppressor function and protect against intestinal inflammation.

Purpose of the Study:

• To elucidate the mechanism by which RORγt regulates Treg function.
• To investigate the role of RORγt in maintaining Foxp3 expression and suppressor function in colonic Tregs.

Main Methods:

• Utilized RORγt-deficient Tregs in a mouse model of colitis (adoptive transfer of CD45RBhi cells into Rag1-/- mice).
• Generated Treg-specific RORγt and T-bet double-deficient gene knockout mice.
• Assessed Foxp3 expression, T-bet and IFN-γ upregulation, Treg suppressor function, and colitis severity.

Main Results:

• RORγt deficiency in Tregs resulted in loss of Foxp3 expression, upregulation of T-bet and IFN-γ, and a Th1-like effector phenotype.
• RORγt-deficient Tregs exhibited impaired suppressor function and failed to ameliorate colitis, leading to severe disease and mortality.
• Deletion of T-bet in RORγt-deficient Tregs restored Foxp3 expression, suppressor function, and prevented colitis onset.

Conclusions:

• RORγt is essential for maintaining the immunosuppressive function of colonic Tregs.
• RORγt exerts its function by repressing T-bet expression, thereby preventing a Th1-like cell fate.
• Targeting the RORγt-T-bet axis offers a potential therapeutic strategy for intestinal inflammatory diseases.