Uptake through glycoprotein 2 of FimH(+) bacteria by M cells initiates mucosal immune response.
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.
Hase
Koji
K
Laboratory for Epithelial Immunobiology, Research Center for Allergy and Immunology, RIKEN, Kanagawa 230-0045, Japan.
Kawano
Kazuya
K
Nochi
Tomonori
T
Pontes
Gemilson Soares
GS
Fukuda
Shinji
S
Ebisawa
Masashi
M
Kadokura
Kazunori
K
Tobe
Toru
T
Fujimura
Yumiko
Y
Kawano
Sayaka
S
Yabashi
Atsuko
A
Waguri
Satoshi
S
Nakato
Gaku
G
Kimura
Shunsuke
S
Murakami
Takaya
T
Iimura
Mitsutoshi
M
Hamura
Kimiyo
K
Fukuoka
Shin-Ichi
S
Lowe
Anson W
AW
Itoh
Kikuji
K
Kiyono
Hiroshi
H
Ohno
Hiroshi
H
D018830:Adhesins, Escherichia coli / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D000818:Animals; D000942:Antigens, Bacterial / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D002460:Cell Line; D004847:Epithelial Cells / Q000276:immunology* / Q000378:metabolism; D004926:Escherichia coli / Q000276:immunology / Q000378:metabolism; D036781:Fimbriae Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D058851:GPI-Linked Proteins; D006023:Glycoproteins; D006367:HeLa Cells; D006801:Humans; D018928:Immunity, Mucosal / Q000276:immunology*; D007422:Intestines / Q000166:cytology; D008562:Membrane Glycoproteins / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D010581:Peyer's Patches / Q000166:cytology* / Q000276:immunology; D012486:Salmonella typhimurium / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D013379:Substrate Specificity
D018830:Adhesins, Escherichia coli; D000942:Antigens, Bacterial; C489339:GP2 protein, human; D058851:GPI-Linked Proteins; D006023:Glycoproteins; C495998:Gp2 protein, mouse; D008562:Membrane Glycoproteins; C058769:fimH protein, E coli; D036781:Fimbriae Proteins