Foxp3+ regulatory T cells restrain pathogenic RORγt+ group 3 ILC-mediated colitis (MUC8P.728)

Abstract

Abstract IL-10 receptor beta (IL-10Rb) is a common receptor chain for both IL-10 and IL-22. Since IL-10 is a protective cytokine that restrains inflammatory responses and IL-22 signaling is required for epithelial cell-dependent tissue repair, targeted deletion of Il10rb should greatly exacerbate inflammatory bowel disease (IBD). Unexpectedly, we found that Il10rb-/- mice are completely resistant to development of spontaneous colitis. In contrast, Il10-/- mice develop IBD by 12 weeks of age and harbor a large number of IL-22-producing RORgt+ innate lymphoid cells (ILCs). Using a CD45RBhi T cell transfer model, we found that induction of intestinal inflammation requires the presence of gut resident RORgt+ ILCs. The IL-22-producing ILCs are essential to perpetuate the disease process initiated by the T cells. Furthermore, Foxp3+ Tregs directly inhibit ILC expression of IL-23R and other tissue injury sensors, thereby suppressing innate cell-driven colitis. Our study has uncovered a novel immune network that maintains intestinal homeostasis.