Type 3 Innate Lymphoid Cells Maintain Intestinal Epithelial Stem Cells After Tissue Damage

Disruption of the intestinal epithelial barrier allows bacterial translocation and predisposes to destructive inflammation. To ensure proper barrier composition, crypt-residing stem cells continuously proliferate and replenish all types of intestinal epithelial cells within days. As a consequence of the high mitotic activity of stem cells, the intestines are highly sucseptible to chemotherapy-induced damage. The cellular mechanisms that control tissue protection and mucosal healing in response to intestinal damage are incompletely understood. Type 3 innate lymphoid cells (ILC3) are regulators of homeostasis and tissue responses to infection at mucosal surfaces. Therefore, we hypothesized that ILC3 could be involved in intestinal epithelial recovery after insult. We demonstrate that ILC3 are required for epithelial STAT3 activation in response to small intestinal tissue damage inflicted by the chemotherapeutic agent methotrexate (MTX). Multiple cytokines are increased in distinct subsets of ILC3 early after MTX and absence of ILC3 leads to increased pathology and severe damage to the intestinal crypts. Using ILC3-deficient Lgr5 reporter mice we show that the maintenance of intestinal stem cells after damage is severely impaired in the absence of ILC3. These data unveil a novel function of ILC3 in limiting tissue damage by preserving tissue-specific stem cells.