Dysregulation of Wnt/ß-catenin signaling contributes to intestinal inflammation through regulation of group 3 innate lymphoid cells.

RORγt+ group 3 innate lymphoid cells (ILC3s) are essential for intestinal homeostasis. Dysregulation of ILC3s has been found in the gut of patients with inflammatory bowel disease and colorectal cancer, yet the specific mechanisms still require more investigation. Here we observe increased ß-catenin in intestinal ILC3s from inflammatory bowel disease and colon cancer patients compared with healthy donors. In contrast to promoting RORγt expression in T cells, activation of Wnt/ß-catenin signaling in ILC3s suppresses RORγt expression, inhibits its proliferation and function, and leads to a deficiency of ILC3s and subsequent intestinal inflammation in mice. Activated ß-catenin and its interacting transcription factor, TCF-1, cannot directly suppress RORγt expression, but rather alters global chromatin accessibility and inhibits JunB expression, which is essential for RORγt expression in ILC3s. Together, our findings suggest that dysregulated Wnt/ß-catenin signaling impairs intestinal ILC3s through TCF-1/JunB/RORγt regulation, further disrupting intestinal homeostasis, and promoting inflammation and cancer.

The Interaction between Lymphoid Tissue Inducer-Like Cells and T Cells in the Mesenteric Lymph Node Restrains Intestinal Humoral Immunity.

Lymphoid tissue inducer (LTi)/LTi-like cells are critical for lymphoid organogenesis and regulation of adaptive immunity in various tissues. However, the maintenance and regulation mechanisms of LTi-like cells among different tissues are not clear yet. Here, we find that LTi-like cells from different tissues display heterogeneity. The maintenance of LTi-like cells in the mesenteric lymph node (mLN), but not the gut, requires RANKL signaling from CD4+ T cells. LTi-like cells from the mLN, but not the gut, could in turn inhibit the development of T follicular helper cells and subsequent humoral responses during intestinal immunization in an ID2- and PD-L1-dependent manner. Together, our findings implicate that the interaction between LTi-like cells and T cells in the mLN could precisely control the intestinal mucosal adaptive immune response.