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

ROR gamma t+ 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 beta-catenin in intestinal ILC3s from inflammatory bowel disease and colon cancer patients compared with healthy donors. In contrast to promoting ROR gamma t expression in T cells, activation of Wnt/beta-catenin signaling in ILC3s suppresses ROR gamma t expression, inhibits its proliferation and function, and leads to a deficiency of ILC3s and subsequent intestinal inflammation in mice. Activated beta-catenin and its interacting transcription factor, TCF-1, cannot directly suppress ROR gamma t expression, but rather alters global chromatin accessibility and inhibits JunB expression, which is essential for ROR gamma t expression in ILC3s. Together, our findings suggest that dysregulated Wnt/beta-catenin signaling impairs intestinal ILC3s through TCF-1/JunB/ROR gamma t regulation, further disrupting intestinal homeostasis, and promoting inflammation and cancer. ROR gamma t+ group 3 innate lymphoid cells are intimately involved in intestinal homeostasis, their dysregulation is linked to inflammatory gut diseases. Here the authors show that dysregulated Wnt/beta-catenin signalling contributes to disturbed regulation of group 3 innate cells and intestinal inflammation.