Microbiota activation and regulation of innate and adaptive immunity

Abstract

The human host has coevolved with the collective of bacteria species, termed microbiota, in a complex fashion that affects both innate and adaptive immunity. Differential regulation of regulatory T-cell and effector T-cell responses are a direct result of specific microbial species present within the gut, and this relationship is subject to dysregulation during inflammation and disease. The microbiota varies widely between individuals and has a profound effect on how one reacts to various environmental stimuli, particularly if a person is genetically predisposed to an immune-mediated inflammatory disorder such as inflammatory bowel disease (IBD), including Crohn's disease (CD) and ulcerative colitis (UC). Approximately, half of all CD patients have elevated antibodies to CBir1, a microbiota flagellin common to mice and humans, demonstrating flagellins as immunodominant antigens in the intestines. This review focuses on the use of flagellins as probes to study microbiota-specific responses in the context of health and disease as well as probes of innate and adaptive responses employed by the host to deal with the overwhelming bacterial presence of the microbiota.

Keywords: B cells; IBD; IgA; T cells; flagellin; microbiota.

Fig. 1. IgA and gut homeostasis

SIgA communicates luminal contents to the lamina propria by sampling commensals and presenting them to tolerogenic DCs, which have a propensity to induce IgA class switching, via a specialized receptor on M cells. Foxp3⁺ Tregs are major T-helper cells involved in IgA production and IgA⁺ B-cell survival in the lamina propria. IgA⁺ plasma cells can also express the antimicrobial mediators TNF-α and iNOS to act as an effector cell in the lamina propria. The multifaceted IgA system acts to maintain an anti-inflammatory setting by compartmentalizing microbial responses to the mucosal immune system to circumvent a systemic response to the microbiota.

Fig. 2. T-regulatory/T-effector cell balance in the intestine

Differential expression of microbial species and components contribute to the balance of T-effector cells (Teff) and T-regulatory cells (Tregs) in the lamina propria. SFB colonization is marked by increased SAA production and augmented Th17 cells. Colonization of the colon with Clostridia XIVa family members is associated with increased TGF-β from the epithelium and augmented Tregs. Numerous additional signals contribute to the balance of Teff/Treg including levels of SCFAs and TLR ligand interactions.

Fig. 3. Structure of CBir1 and related flagellins

The predicted structure of CBir1 and Lachnospriaceae A4 Fla2 flagellins is similar the previously defined fliC of S. typhimurium, including a TLR5 binding site, depicted in red. Figure used with permission (103).