Sequential activity of innate and adaptive lymphocytes supports non-inflammatory gut microbial commensalism

Abstract The mammalian gut is colonized by trillions of microorganisms termed the “microbiota”, which have a mutually beneficial relationship with their host. In normal individuals, the gut microbiota matures after birth to a state of balanced commensalism that is marked by the absence of adverse inflammation. Both innate lymphoid cells (ILCs) and antigen-specific conventional T cells contribute to containment and clearance of microbial pathogens. But how these two major lymphoid cell populations help shape the mature commensal (non-pathogenic) microbiome and maintain tissue homeostasis has not been determined. Using advanced multiplex quantitative imaging methods, here we show that in the absence of adaptive lymphocytes, IL-23 induced by specific commensal bacteria such as Segmented Filamentous Bacteria (SFB) persistently activates RORgt+ group 3 innate lymphoid cells (ILC3s) in the ileum to produce IL-22, which induces STAT3 activation in virtually all epithelial cells, contributing to production of molecules such as anti-microbial peptides that protect the tissue from microbial damage. The distinct roles of ILCs in handling gut microbes play out in normal mice during development. The pSTAT3 signature is absent after birth, which is followed by microbial colonization and strong ILC3 activation and an extensive epithelial pSTAT3 signature upon weaning. This innate immune activity is subsequently extinguished as adaptive CD4+ T cell immunity develops in response to the expanding commensal burden. Our findings provide new insights into how innate and adaptive lymphocytes sequentially operate during normal development to establish steady state commensalism.