Abstract
Despite studies indicating the effects of IL-21 signaling in intestinal inflammation, its roles in intestinal homeostasis and infection are not yet clear. Here, we report potent effects of commensal microbiota on the phenotypic manifestations of IL-21 receptor deficiency. IL-21 is produced highly in the small intestine and appears to be critical for mounting an IgA response against atypical commensals such as segmented filamentous bacteria and Helicobacter, but not to the majority of commensals. In the presence of these atypical commensals, IL-21R-deficient mice exhibit reduced numbers of germinal center and IgA+ B cells and expression of activation-induced cytidine deaminase in Peyer’s patches as well as a significant decrease in small intestine IgA+ plasmablasts and plasma cells, leading to higher bacterial burdens and subsequent expansion of Th17 and Treg cells. These microbiota-mediated secondary changes in turn enhance T cell responses to an oral antigen and strikingly dampen Citrobacter rodentium-induced immunopathology, demonstrating a complex interplay between IL-21-mediated mucosal immunity, microbiota, and pathogens.
Highlights
Interleukin-21 (IL-21) is a pleotropic cytokine that regulates a wide range of innate and adaptive immune responses and exerts major effects on the development of autoimmune and inflammatory disorders.[1]
There was approximately a fourfold decrease in the number of germinal center B cells (CD19+CD38−GL7+CD95+) in the Peyer’s patches (PPs) of IL-21R KO mice compared to WT littermates, whereas the number of T follicular helper (Tfh) cells remained unchanged (Fig. 2b, c)
We found an enhanced segmented filamentous bacteria (SFB) burden in the stool and the terminal ileum of IL-21R KO mice compared to WT littermates (Fig. 3e), suggesting that enhanced SFB contact with the epithelium may contribute to the enhanced T helper 17 (Th17) responses in the small intestine lamina propria (SILP) seen in these mice
Summary
Interleukin-21 (IL-21) is a pleotropic cytokine that regulates a wide range of innate and adaptive immune responses and exerts major effects on the development of autoimmune and inflammatory disorders.[1]. IL-21 contributes to Th17 and Tfh cell generation, but it impedes development of T helper 1 (Th1) and regulatory T (Treg) cells.[3,8,9] IL-21 stabilizes and expands the Th17 cell population by augmenting IL-23 receptor expression and inducing the expression of RORγt, a master regulator of Th17 differentiation.[10] In addition, IL-21-mediated suppression of Treg cell expansion is via inhibition of IL-2 production by conventional CD4 T cells.[11] IL-21 has been reported to inhibit the expansion of T follicular regulatory (Tfr) cells, which is associated with decreased expression of the IL-2 receptor α chain, CD25.12
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