LAUSR

Group 3 innate lymphoid cells (ILC3s) are innate immune effectors that contribute to host defense. Whether ILC3 functions are stably modified after pathogen encounter is unknown. Here, we assess the impact of a time-restricted enterobacterial challenge to long-term ILC3 activation in mice. We found that intestinal ILC3s persist for months in an activated state after exposure to Citrobacter rodentium. Upon rechallenge, these “trained” ILC3s proliferate, display enhanced interleukin-22 (IL-22) responses, and have a superior capacity to control infection compared with naïve ILC3s. Metabolic changes occur in C. rodentium–exposed ILC3s, but only trained ILC3s have an enhanced proliferative capacity that contributes to increased IL-22 production. Accordingly, a limited encounter with a pathogen can promote durable phenotypic and functional changes in intestinal ILC3s that contribute to long-term mucosal defense. Description Trained ILC3: Better, faster, stronger! Type 3 innate lymphoid cells (ILC3s) are enriched in the intestinal tract and play important roles in mucosal homeostasis, host defense, and the organization of lymphoid tissues. Although certain innate immune cell populations can adopt new long-term phenotypes in response to inflammatory signals (“trained immunity”), whether this is also true of ILC3s is unclear. Serafini et al. report that after mice were infected with Citrobacter rodentium, a subset of activated ILC3s persisted for months. These “trained” ILC3s (Tr-ILC3s) showed superior activation and controlled infection better than “naïve” ILC3s after pathogen rechallenge. The initial encounter with C. rodentium durably rewires the metabolic pathways of Tr-ILC3s, endowing them with an enhanced capacity to proliferate and secrete cytokines such as interleukin-22. —STS Intestinal group 3 innate lymphoid cells have memory-like properties after bacterial infection that contribute to long-term mucosal defense.