LAUSR

IL-21 has been shown to regulate IgA production. However, how it regulates gut microbiota and intestinal homeostasis through regulation of IgA is still not fully understood. A study by Cho et al. in this issue of Mucosal Immunology demonstrates that IL-21 promotes intestinal IgA responses to atypical commensals to reshape the mucosal immunity and microbiota. The intestines harbor a microbiota consisting of 100 trillion microbes in humans. Over millions of years of evolution, hosts have developed multiple regulatory mechanisms to keep the vast microbial community in check. Gut microbiota, in turn, has a major impact on host systems, particularly on the development of the intestines and the immune system. Despite the enormous bacterial challenge, the intestines live in harmony with the microbiota, in part due to interactions of the microbiota with the host to maintain a symbiotic relationship. The host senses and responds to the microbiota through coordinated immune responses that are not overly aggressive towards commensal microbes, but remain primed to defend against invading pathogens. Among the multiple regulatory mechanisms that have been evolved by the host, Th17 cells and intestinal IgA (sIgA), which are enriched in intestines, have crucial roles in the maintenance of intestinal homeostasis against the microbiota. As the most abundant antibody isotype in the intestine, IgA not only functions to neutralize and aid in clearance of toxins and extracellular pathogens through high affinity binding, but also binds to commensal bacteria through the Fab as well as through glycosyl interactions to limiting contact of gut microbiota and its antigens with the hosts. IgA regulates the microbiota, and gut bacteria in turn adapt to IgA by altering their gene expression patterns to promote survival and homeostasis within the intestines. The high level of IgA production in the intestines is driven by microbial colonization, which is exemplified by the fact that germ-free mice have low levels of IgA and IgA-producing B cells with subsequent recolonization by microbiota restoring IgA production. Multiple mechanisms regulate intestinal IgA responses, including both T cell-dependent and T cellindependent pathways. Although the relative contribution of T cell-dependent and T cell-independent regulation of intestinal IgA responses is still not completely understood, a recent report demonstrated that bacteria in the small intestine but not indigenous colonic bacteria dictated induction of specific IgA in a T cell-independent manner, although the mechanisms remain unclear. Most commensals elicited strong T-independent responses that originated from the B1b and B2 cells, but excluded natural antibacterial B1a specificities. However, atypical commensals, such as segmented filamentous bacteria (SFB), Mucispirillum, and Helicobacter, evaded T cell-independent but elicited T celldependent IgA responses. However, how the differential IgA responses to atypical commensals contribute to intestinal homeostasis are still not fully clear. The intestinal tract has been shown to be a natural site for the development of Th17 cells, which produce a distinct set of cytokines, including IL-17, IL-21, and IL-22. Intestinal Th17 cell development is stimulated by specific species of microbiota, with SFB being identified as one of such stimulators. Interestingly, SFB also stimulates intestinal IgA production. Although both proand anti-inflammatory functions of Th17 cells have been demonstrated in different experimental systems, the enrichment of Th17 cells in the intestines suggests a role for these cells in mucosal homeostasis and more specifically in the containment of the vast local microbiota. Th17 cells induce mucosal IgA production in the intestines directly or through conversion to T follicular helper (Tfh) cells via production of IL-17 and IL-21. Intestinal IgA is substantially reduced in IL-17R, IL-21, and IL-21R mice when compared to wild-type mice, and IL-21 induces IgA class-switch recombination in cooperation with TGFβ and retinoic acid in vitro. However, as IL-21 is predominantly produced by Th17 and Tfh cells, it remains unclear which source of IL-21 is most potent in inducing intestinal IgA production. It is also unclear how IL-21 regulates IgA responses to atypical commensal bacteria. Furthermore, both pro-inflammatory and anti-inflammatory functions for IL-21 in the intestines have been reported, thus, how it affects intestinal homeostasis remains unclear. In this issue of Mucosal Immunology, Cho et al. found that IL-21 was critical for an IgA response against atypical commensals but not to the majority of commensals. Additionally, a defective IgA response to atypical commensals in the absence of IL-21 signaling led to higher bacterial burdens and subsequent expansion of Th17 cells. Strikingly, the microbiota-mediated secondary changes enhanced T cell responses in the mucosa and dampened enteric infectioninduced immunopathology in the intestines. Although both Th17 and Tfh cells produce high levels of IL-21, how these T cells produce IL-21 in response to microbiota in the intestines is still not well established. Cho et al. found that CD4 T cells are the main source of IL-21 production in the intestine, mainly in the Peyer’s patches (PPs) and small intestine lamina propria (SILP). Atypical commensal SFB colonization stimulated production of IL-21, mainly in CD4 T cells. Surprisingly, although