Microbiota-dependent IL-21 signaling regulates intestinal immune cell homeostasis and immunopathology to infection

Despite studies indicating a role for IL-21 in intestinal inflammation, how it precisely affects intestinal homeostasis and immunity to infection is not yet clear. In this study, we report a potent effect of commensal microbiota on the phenotypic manifestations of IL-21 receptor deficiency. IL-21 is expressed highly by CD4 T cells of Peyer’s patches (PPs) and small intestine lamina propria (LP) and strongly induced by co-housing with SFB-positive mice. Mice deficient in IL-21 receptor exhibit reduced numbers of GC B cells, B cell expression of AID, and IgA + B cell populations in PPs, consistent with the known roles for IL-21 in B cell function. Consequently, IL-21R KO mice show a significant reduction in IgA + plasmablasts and plasma cells in the small intestine LP. Interestingly, microbiota-dependent increases in RORgt + T cells and Treg cells are observed in the small intestine of IL21-R KO mice. Neither the Th1 nor RORgt + ILC populations are altered in the KO mice intestine compared to WT mice. Demonstrating a critical role of IL-21 signaling in immunopathology during Citrobacter rodentium infection, IL-21 receptor deficiency leads to strikingly reduced tissue pathology without affecting bacterial clearance. This reduced immunopathology likely results from dampened production of IFNg, IL-12, and IL-1b that promote severe immunopathology/lethality. Taken together, we demonstrate the regional and pleotropic effects of IL-21 signaling that fine-tunes intestinal mucosal immunity in a microbiota-dependent manner, which has significant implication for anti-IL-21 therapy to treat inflammatory bowel disease.