Trained ILC3 Responses Promote Intestinal Defense

Group 3 innate lymphoid cells (ILC3) are innate immune effectors that contribute to host defense. Whether ILC3 functions are stably modified following pathogen encounter is unknown. Here we assess the impact of a time-restricted enterobacterial challenge to long-term ILC3 activation. We found that intestinal ILC3 persist for months in an activated state following exposure to Citrobacter rodentium. Upon rechallenge, these “trained” ILC3 proliferate, display enhanced interleukin (IL)-22 responses, and have a superior cell-intrinsic capacity to control infection compared to naïve ILC3. Metabolic changes occur in C. rodentium-exposed ILC3 but only trained ILC3 have enhanced proliferative capacity that contributes to elevated IL-22 production. Accordingly, a limited encounter with a pathogen can promote durable phenotypic and functional changes in intestinal ILC3 that contribute to long-term mucosal defense. 24 samples from murine small intestine