CCR6 Deficiency Impairs IgA Production and Dysregulates Antimicrobial Peptide Production, Altering the Intestinal Flora

Abstract

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.

Anatomical Uniqueness of the Mucosal Immune System (GALT, NALT, iBALT) for the Induction and Regulation of Mucosal Immunity and Tolerance

“…Whereas the cryptopatches primarily support innate immune responses due to a paucity of B and T cells, ILFs are important sites for the induction of adaptive immune responses, particularly the differentiation of IgA-producing B cells responding to the gut microbiota or food antigens [88,89]. Interestingly, ILFs are also an important source of T-cell-independent antimicrobial IgA [89], with no direct relation to the immune responses occurring in Peyer's patches [90].…”

“…Recent work has broadened our understanding of the role of ILFs, and a general consensus is that they act in a tolerogenic manner to control intestinal immune responses by generating both IgA-secreting plasma cells and regulatory T cells [91,92], both of which are involved in the noninflammatory containment of commensal organisms. Conversely, the absence of ILFs leads to poor IgA production and a dramatic expansion of the intestinal microbiota [88]. Thus ILFs are powerhouses of IgA production in response to microbial antigens [90].…”

“…For example, dome epithelial cells express CCL20 and CCL9 [100], which attract subsets of immature CCR6-and CCR1-expressing DCs to the subepithelial dome of Peyer's patches [100]. CCL20 is also important for attracting B cells to the dome, where they interact with CD11b 1 DCs and isotype-switch to IgA [88,122]. Another chemokine, CXCL16, is also expressed by the dome epithelium of Peyer's patches, ILFs, and cecal patches [123], whereas its receptor, CXCR6, is observed on subpopulations of activated and memory CD4 1 and CD8 1 T cells in the dome region.…”

“…The process by which naïve B cells become activated and switch to IgA is very dependent on the structural architecture and cell types in GALT. In particular, activated B cells use the chemokine receptor CCR6 to migrate to the dome region of Peyer's patches, where they interact with DCs that prompt B cells to undergo isotype-switching to IgA [88]. Switching to IgA requires B cells to encounter active TGF-β, which is converted from the latent form by integrin αvβ8-expressing DCs in the dome epithelium [99].…”

CCR6-CCL20 Axis in IBD: What have we learnt in the past 20 years?

“…Further they reported decreased numbers of ILC within isolated lymphoid follicles (ILFs) similar to mothers against decapentaplegic bringing forth a marked reduction in IL-22 secretion which negatively impacts upon anti-microbial peptide production by the IEC. Absence of CCR6 functionality also leads to higher levels of Alcaligenes in PP and filamentous bacteria thriving within the epithelium delineating a role for CCR6 in regulating intestinal symbiotic relationships [46].…”