In the intestine, crypt-residing stem cells proliferate continuously to replenish the epithelial barrier. Because of this high mitotic activity, the gut epithelium is often affected by anticancer therapies. In The Journal of Experimental Medicine, Cupedo and colleagues use a model of methotrexate-induced self-resolving damage in the small intestine to show that type 3 innate lymphoid cells (ILC3 cells) are required for the proliferation and regeneration of epithelial cells. After treatment with methotrexate, both NKp46+ ILC3 cells and CCR6+ ILC3 cells are activated and express the cytokines IL-22, TNF, LTβ and IFN-γ, and ILC3-deficient RORγt-deficient mice have more damage in the intestinal crypt and loss of Lgr5+ intestinal stem cells than do wild-type mice. Blockade of IL-22 also leads to loss of intestinal stem-cell maintenance in the duodenum. The role of ILC3 in preserving intestinal stem cells could be harnessed to minimize side effects in patients undergoing cytotoxic therapy.

J. Exp. Med. (21 September 2015) doi:10.1084/jem.20150318