Endocytosis of commensal antigens by intestinal epithelial cells regulates mucosal T cell homeostasis

Abstract

Commensal bacteria influence host physiology, without invading host tissues. We show that proteins from segmented filamentous bacteria (SFB) are transferred into intestinal epithelial cells (IECs) through adhesion-directed endocytosis that is distinct from the clathrin-dependent endocytosis of invasive pathogens. This process transfers microbial cell wall–associated proteins, including an antigen that stimulates mucosal T helper 17 (TH17) cell differentiation, into the cytosol of IECs in a cell division control protein 42 homolog (CDC42)–dependent manner. Removal of CDC42 activity in vivo led to disruption of endocytosis induced by SFB and decreased epithelial antigen acquisition, with consequent loss of mucosal TH17 cells. Our findings demonstrate direct communication between a resident gut microbe and the host and show that under physiological conditions, IECs acquire antigens from commensal bacteria for generation of T cell responses to the resident microbiota.

Microbiology and immunology: An ideal partnership for a tango at the gut surface—A tribute toPhilippe Sansonetti

“…Atarashi et al further suggested that the actin reorganisation that is associated with the attachment of SFB to epithelial cells could promote SAA transcription (Atarashi et al, ). A very recent study also links the induction of TH17 cells with SFB‐induced actin rearrangement in epithelial cells (Ladinsky et al, ). This study used electron tomography to analyse the synapse between SFB and epithelial cells and demonstrated that proteins, including the SFBNYU‐03340 immunogenic protein that is targeted by the TH17 response (Yang et al, ), was transferred into epithelial cells trough adhesion‐triggered endocytosis.…”

“…Surprisingly, however, inactivation of Cdc42 in epithelial cells only partially impaired the epithelial transcriptomic response induced upon colonisation by SFB, and notably, it did not affect the transcription of genes encoding SAAs or DUOX2. It also failed to impair the IgA response induced by SFB (Ladinsky et al, ). Further studies are, therefore, necessary to delineate the exact role of adhesion‐induced endocytosis and epithelial actin rearrangement in driving the spectrum of immune responses stimulated by SFB.…”

“…Further studies are, therefore, necessary to delineate the exact role of adhesion‐induced endocytosis and epithelial actin rearrangement in driving the spectrum of immune responses stimulated by SFB. Of note, adhesion‐triggered endocytosis was not observed with other commensal or pathogenic strains, including strains that induce TH17 responses, suggesting that this mode of communication with epithelial cells is specific to SFB (Ladinsky et al, ). TH17 cells elicited by SFB may thus differ from those induced by pathogens.…”

Intestinal epithelial cells: at the interface of the microbiota and mucosal immunity

“…72,73 This has been hypothesized to occur via mechanosensing of microbial contact, and a recent study has shown that in the case of segmented filamentous bacteria (SFB), the transfer of SFB antigens through IECs via microbial adhesion-triggered endocytosis (MATE) plays a pivotal role. 74 Another recent study shows that epithelial sensing of dietary vitamin A through retinoic acid receptor b is also required for IEC expression of SAAs. 75 Perhaps less appreciated, glucocorticoids (GCs) and neurotransmitters are also abundantly produced by epithelial cells in the gut.…”

Understanding immune–microbiota interactions in the intestine

“…Bacterially derived polysaccharides such as polysaccharide A from B. fragilis, β ‐glucan/galactan polysaccharides from Bifidobacterium bifidum or crude carbohydrate preparations from H. hepaticus can prime Treg or IL‐10 production. Intriguingly, atypical antigen acquisition pathways have also been shown to be important for SFB‐induced Th17 development. Collectively, these studies demonstrate that the intestinal immune system can be activated by a diverse array of microbial taxa through a variety of distinct mechanisms, highlighting a large degree of redundancy in the processes which help to maintain these mutualistic relationships.…”