Identification of subepithelial mesenchymal cells that induce IgA and diversify gut microbiota

Abstract

Immunoglobulin A (IgA) maintains a symbiotic equilibrium with intestinal microbes. IgA induction in the gut-associated lymphoid tissues (GALTs) is dependent on microbial sampling and cellular interaction in the subepithelial dome (SED). However it is unclear how IgA induction is predominantly initiated in the SED. Here we show that previously unrecognized mesenchymal cells in the SED of GALTs regulate bacteria-specific IgA production and diversify the gut microbiota. Mesenchymal cells expressing the cytokine RANKL directly interact with the gut epithelium to control CCL20 expression and microfold (M) cell differentiation. The deletion of mesenchymal RANKL impairs M cell-dependent antigen sampling and B cell-dendritic cell interaction in the SED, which results in a reduction in IgA production and a decrease in microbial diversity. Thus, the subepithelial mesenchymal cells that serve as M cell inducers have a fundamental role in the maintenance of intestinal immune homeostasis.

M cell-dependent antigen uptake on follicle-associated epithelium for mucosal immune surveillance

“…Expressions of these chemokines are mainly controlled by signaling through the LTβR and receptor activator of nucleic factor-kappa B (RANK; TNFRSF11A). Genetic ablation of RANK signaling diminishes Ccl20 expression in gut-associated lymphoid tissue (GALT) [18]. In human, the clusters of lymphocytes are identified in small intestine at 14–16 weeks of gestation, and PPs are microscopically observable at gestational age of 24 weeks [19].…”

“…The maturation of MALT also necessitates antigen transport via M cells. In support of this idea, mice lacking M cells because of deficiency in RANK in intestinal epithelium or nucleic factor-kappa B ligand (RANKL) in sub-epithelial mesenchymal cells [known as M cell inducer (MCi)] of GALTs display the reduced size of PPs in association with inactivation of the germinal center reaction [18, 22]. Thus, FAE-intrinsic Notch signaling as well as antigen exposure is essential for the maturation of GALTs.…”

“…As described earlier, RANKL is provided from stromal MCi cells residing underneath the FAE of GALT (Fig. 2) [18]. Because intestinal epithelial cells constitutively express a RANKL receptor, RANK (TNFRSF11A), intraperitoneal administration of recombinant RANKL ectopically induces differentiation of the M cell-like GP2 + cells in the intestinal villous region [43, 44].…”

TGFβ signaling in germinal center B cells promotes the transition from light zone to dark zone

“…Activated pre-GCBs up-regulate Ccr6, which guides the cells to the Ccl20-rich SED in PPs (Reboldi et al, 2016; Nagashima et al, 2017). TGFβ signaling is thought to promote IgA induction in activated pre-GCBs in the SED of PPs.…”

Investigação do microbioma intestinal em camundongos deficientes em CRAMP submetidos à sepse experimental

“…IgA está envolvida no equilíbrio intestinal e defesa contra patógenos. (34) Cerca de 100 trilhões de micróbios compõem o vasto microbioma humano que, em estado saudável, contribui para manutenção da barreira microbiológica e fisiológica. (29,35) A microbiota intestinal pode influenciar aspectos biológicos do hospedeiro, como metabolismo, fisiologia e imunidade.…”