Thurairajah, B.; Westfall, S.; Chiggiato, L.; Keogh, L.; Sinha, A.; Olsen, K.; Tafesse, Y.; Lypaczewski, P.; Fontes, G.; Shapiro, B. J.; Cousineau, B.; Gruenheid, S.; Vermijlen, D.; Castagner, B.; Saliba, A.-E.; King, I. L.

Early postnatal life is a highly dynamic period in which the intestine is inundated with billions of microbes that not only battle for colonization, but also strongly influence immune system function and long-term health. This brief period of development provides a window of opportunity to imprint resilience against disease, yet the intercellular dialogue that dictates tissue protection are only beginning to be discovered. By performing a kinetic analysis of immune cell activation in the colon of mice from early life to adulthood, we identified transient activation of a microbiota-dependent type 3 immune response during the weaning period. This response was characterized by a selective increase in IL-17 production by fetal-derived gdT cells that occurred in an IL-1 receptor-dependent, cell-intrinsic manner. The subsequent differentiation of IL-10 producing Rorgt+ T regulatory cells extinguished IL-17 production by gdT cells and prevented immunopathology. Microbial gain-of-function approaches determined that colonic gdT cell activation occurred in response to passive acquisition of C. difficile at birth. In turn, IL-17 limited C. difficile growth and intestinal barrier breach by the commensal microbiota. Collectively, our results reveal how an agile immune cell network meets the demands of a maturing microbiota to support gut health during early life.