Uptake through glycoprotein 2 of FimH+ bacteria by M cells initiates mucosal immune response

Abstract

The mucosal immune system forms the largest part of the entire immune system, containing about three-quarters of all lymphocytes and producing grams of secretory IgA daily to protect the mucosal surface from pathogens. To evoke the mucosal immune response, antigens on the mucosal surface must be transported across the epithelial barrier into organized lymphoid structures such as Peyer's patches. This function, called antigen transcytosis, is mediated by specialized epithelial M cells. The molecular mechanisms promoting this antigen uptake, however, are largely unknown. Here we report that glycoprotein 2 (GP2), specifically expressed on the apical plasma membrane of M cells among enterocytes, serves as a transcytotic receptor for mucosal antigens. Recombinant GP2 protein selectively bound a subset of commensal and pathogenic enterobacteria, including Escherichia coli and Salmonella enterica serovar Typhimurium (S. Typhimurium), by recognizing FimH, a component of type I pili on the bacterial outer membrane. Consistently, these bacteria were colocalized with endogenous GP2 on the apical plasma membrane as well as in cytoplasmic vesicles in M cells. Moreover, deficiency of bacterial FimH or host GP2 led to defects in transcytosis of type-I-piliated bacteria through M cells, resulting in an attenuation of antigen-specific immune responses in Peyer's patches. GP2 is therefore a previously unrecognized transcytotic receptor on M cells for type-I-piliated bacteria and is a prerequisite for the mucosal immune response to these bacteria. Given that M cells are considered a promising target for oral vaccination against various infectious diseases, the GP2-dependent transcytotic pathway could provide a new target for the development of M-cell-targeted mucosal vaccines.

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

“…The colonic ILFs in RANKL Ϫ/Ϫ mice included some mature ILFs covered by a FAE, demonstrating that the full spectrum of ILF development can be completed in the colon in the absence of RANKL. However, M cells, as identified by their expression of the M cell-specific marker GP2, 20 were present in the FAE overlaying colonic ILFs in RANKL ϩ/Ϫ mice, but not in RANKL Ϫ/Ϫ mice ( Figure 4D). We previously showed that differentiation of M cells in the PP FAE requires RANKL.…”

Crohn’s disease specific pancreatic antibodies: clinical and pathophysiological challenges

“…The seminal paper of Hase et al demonstrated GP2 to be involved in the generation of humoral immune responses to molecules of the intestinal content interacting specifically with GP2 on M cells [55]. These findings have led to a better understanding of autoimmunity against GP2 in CrD-specific inflammation and to a dramatic change in the understanding of the physiology of GP2.…”

“…Defective THP synthesis is associated with an elevated susceptibility of mice to urinary tract infections [69]. In this context, the elegant study by Hase et al demonstrated that GP2 selectively binds to a subset of commensal and pathogenic enterobacteria, including E. coli and Salmonella enterica serovar Typhimurium [55]. Akin to THP, this type of binding is mediated by FimH of type I pili on the bacterial outer membrane [70].…”

“…Thus, the identification of GP2 as a specific receptor on microfold (M) cells of intestinal Peyer's patches (PP) by Hase et al ushered in a new age of autoimmunity research in IBD [55][56][57].…”

Serological diagnosis and prognosis of severe acute pancreatitis by analysis of serum glycoprotein 2

“…The self-aggregating, non-digestive autoantigenic GP2 is secreted along with digestive proenzymes and represents a major pancreatic plug component [4,16,[26][27][28]. GP2 does not appear to play a decisive intracellular role during secretion but rather an antimicrobial and immunomodulating one after its release into the intestine despite its reported regulation of acinar endocytosis or ZG assembly [29][30][31][32][33][34][35][36].…”