Lymphoid tissue genesis induced by commensals through NOD1 regulates intestinal homeostasis

Abstract

Intestinal homeostasis is critical for efficient energy extraction from food and protection from pathogens. Its disruption can lead to an array of severe illnesses with major impacts on public health, such as inflammatory bowel disease characterized by self-destructive intestinal immunity. However, the mechanisms regulating the equilibrium between the large bacterial flora and the immune system remain unclear. Intestinal lymphoid tissues generate flora-reactive IgA-producing B cells, and include Peyer's patches and mesenteric lymph nodes, as well as numerous isolated lymphoid follicles (ILFs). Here we show that peptidoglycan from Gram-negative bacteria is necessary and sufficient to induce the genesis of ILFs in mice through recognition by the NOD1 (nucleotide-binding oligomerization domain containing 1) innate receptor in epithelial cells, and beta-defensin 3- and CCL20-mediated signalling through the chemokine receptor CCR6. Maturation of ILFs into large B-cell clusters requires subsequent detection of bacteria by toll-like receptors. In the absence of ILFs, the composition of the intestinal bacterial community is profoundly altered. Our results demonstrate that intestinal bacterial commensals and the immune system communicate through an innate detection system to generate adaptive lymphoid tissues and maintain intestinal homeostasis.

Distinct Developmental Requirements for Isolated Lymphoid Follicle Formation in the Small and Large Intestine

“…14 Sensing of the enteric microflora by nucleotidebinding oligomerization domain protein 1 (NOD1) was identified as a critical signal driving the differentiation of CPs into immature ILFs. 36 Although RANKL Ϫ/Ϫ mice are normally colonized by gut commensals, we previously showed they have less than 2% of the normal number of antigen-sampling M cells compared to wild-type mice. 18 This profound M cell deficit in RANKL Ϫ/Ϫ mice likely results in decreased antigen-sampling of the commensal flora, thereby impairing the NOD1-initiated differentiation of CPs into immature ILFs.…”

Functional and phenotypic heterogeneity of group 3 innate lymphoid cells

“…Cryptopatch‐resident ILC3 maintain the local crypt stem cell pool and regulate tissue repair following inflammation, chemotherapy or transplantation 37, 38, 39. In addition, cryptopatches act as a site for B‐cell recruitment to form mature tertiary lymphoid structures known as isolated lymphoid follicules (ILFs) 36, 40, 41. ILFs are important sites for production of IgA against intestinal bacteria and ILF hyperplasia occurs in the context of inflammation or bacterial outgrowth,41 suggesting that ILFs are ILC3‐regulated inducible lymphoid tissues required for orchestration of local responses to commensal bacteria.…”

Mucosal immunity: aliment and ailments

“…16 Finally, activation of innate immunity via Nod or TLR results in the secretion of anti-microbial peptides, 17 and triggering of Nod1 supports GALT via the generation of isolated lymphoid follicles (ILFs) in the intestinal mucosa. 18 Taken together, these observations highly suggest that activation of innate immunity at the host -microbial interface of the gastrointestinal tract has adapted from inducing infl ammation (tissue damage) to healing and restitution (tissue building). 19 Hence, the overall protective eff ect of innate immunity on the host is through the maintenance of IEC integrity, which is mandatory for the proper metabolic functions of the gastrointestinal tract.…”