Intestinal immunity exists as a complex relationship among immune cells, epithelial cells, and microbiota. CCR6 and its ligand–CCL20 are highly expressed in intestinal mucosal tissues, such as Peyer’s patches (PPs) and isolated lymphoid follicles (ILFs). In this study, we investigated the role of the CCR6–CCL20 axis in intestinal immunity under homeostatic conditions. CCR6 deficiency intrinsically affects germinal center reactions in PPs, leading to impairments in IgA class switching, IgA affinity, and IgA memory B cell production and positioning in PPs, suggesting an important role for CCR6 in T-cell-dependent IgA generation. CCR6 deficiency impairs the maturation of ILFs. In these follicles, group 3 innate lymphoid cells are important components and a major source of IL-22, which stimulates intestinal epithelial cells (IECs) to produce antimicrobial peptides (AMPs). We found that CCR6 deficiency reduces IL-22 production, likely due to diminished numbers of group 3 innate lymphoid cells within small-sized ILFs. The reduced IL-22 levels subsequently decrease the production of AMPs, suggesting a critical role for CCR6 in innate intestinal immunity. Finally, we found that CCR6 deficiency impairs the production of IgA and AMPs, leading to increased levels of Alcaligenes in PPs, and segmented filamentous bacteria in IECs. Thus, the CCR6–CCL20 axis plays a crucial role in maintaining intestinal symbiosis by limiting the overgrowth of mucosa-associated commensal bacteria.
CXCL10 is an IFN-inducible chemokine ligand that binds CXCR3, a receptor that is expressed on lymphocytes; CXCL10 shares the CXCR3 receptor with another two ligands, CXCL9 and CXCL11. Previously, we found that CXCL10−/− mice were more susceptible than wild-type (WT) mice to dengue virus (DENV) infection. In this study, we explored the mechanisms underlying this enhanced susceptibility. We found that viral loads were higher in the brains of CXCL10−/− mice than in WT mice. Presuming a defect in effector lymphocyte migration, we investigated whether recruitment of effector T cells and Ab-secreting cells to the infected tissues were impaired in CXCL10−/− mice. Unexpectedly, compared with WT, CXCL10−/− mice had comparable numbers of total infiltrating T cells, higher numbers of CXCR3+ T cells, and higher numbers of Ab-secreting cells in the brain. Additionally, we found that CXCL10 was induced in neurons following DENV infection and that CXCL10 competed with DENV for binding to cell surface heparan sulfate, a coreceptor for DENV entry, thus inhibiting binding of DENV to neuronal cells. These results demonstrate that the enhanced susceptibility of CXCL10−/− mice to DENV infection is not due to a defect in recruitment of effector lymphocytes but rather to an antiviral activity that promotes viral clearance.
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