M cells are located in the follicle associated epithelium (FAE) of Peyer’s patches (PPs) in the small intestine, where they mediate the uptake and transcytosis of luminal antigens to the underlying lymphoid tissue. Gycoprotein 2 (GP2) is a GPI-anchor protein that was previously thought to be exclusively expressed by pancreatic acinar cells of most mammals. Recent studies reported that GP2 is specifically expressed in M cells among intestinal epithelial cells, and serves as a transcytotic receptor for mucosal antigens. Although UEA-1 (Ulex europaeus agglutinin-1) lectin has been widely applied to detect M cells, this lectin also stains goblet cells. Furthermore, UEA-1 can only bind mouse, but not human, M cells. Thus, GP2 is the first universal M-cell marker in mouse and human. Mouse and human GP2 recombinant proteins selectively bind a subset of commensal and pathogenic enterobacteria, including Escherichia coli and Salmonella spp., by recognizing FimH-expressing type-1-pili on the bacterial outer membrane. GP2 expressed on apical surface of M cells serves as a receptor for type-1-piliated bacteria, and facilitates translocation of these bacteria from the intestinal lumen to lymphoid follicles. Consequently, antigen-specific mucosal immune response to these bacteria is induced. Thus, GP2 plays an important role in mucosal immunosurveillance. Given that M cell are considered a promising target for oral vaccination against diverse infectious diseases, the GP2-dependent transcytotic pathway could provide a new target for development of M-cell-targeted mucosal vaccines.