권미나 (국제백신연구소)

Myoung Ho Jang ^a,b, Mi-Na Kweon ^a,b,c,d, Koichi Iwatani ^a, Masafumi Yamamoto ^a,d,e, Kazutaka Terahara ^d,f, Chihiro Sasakawa ^f,g, Toshihiko Suzuki ^g,h, Tomonori Nochi ^d,f, Yoshifumi Yokota ⁱ, Paul D. Rennert ^j, Takachika Hiroi ^a,d,f, Hiroshi Tamagawa ^a, Hideki Iijima ^a, Jun Kunisawa ^a,d, Yoshikazu Yuki ^d,f, and Hiroshi Kiyono ^a,d,f,k,l

^aDepartment of Mucosal Immunology, Research Institute for Microbial Diseases, Osaka University, Osaka 565-0871, Japan; ^cMucosal Immunology Section, International Vaccine Institute, Seoul 151-818, Korea; ^eDepartment of Oral Medicine, Nihon University, School of Dentistry at Matsudo, Chiba 271, Japan; ^gDivision of Bacteriology, Institute of Medical Science, University of Tokyo, Tokyo 108-8639, Japan; ^hPRESTO (Precursory Research for Embryonic Science and Technology), Japan Science and Technology Corporation (JST), Kawaguchi, Saitama 332-0012, Japan; ⁱFirst Department of Biochemistry, Fukui Medical University, Matsuoka, Fukui 910-1193, Japan; ^jBiogen Incorporated, Cambridge, MA 02142; ^fCore Research for Evolutional Science and Technology (CREST), Japan Science and Technology Corporation (JST), Kawaguchi, Saitama 332-0012, Japan; ^kImmunobiology Vaccine Center, University of Alabama at Birmingham, Birmingham, AL 35294; and ^dDivision of Mucosal Immunology, Institute of Medical Science, University of Tokyo, Tokyo 108-8639, Japan

Communicated by Roy Curtiss, Washington University, St. Louis, MO, February 11, 2004 (received for review September 20, 2003)

M cells located in the follicle-associated epithelium of Peyer''s patches (PP) are shown to be the principal sites for the sampling of gut luminal antigens. Thus, PP have long been considered the gatekeepers of the mucosal immune system. Here, we report a distinct gateway for the uptake of gut bacteria: clusters of non-follicle-associated epithelium-associated Ulex europaeus agglutinin (UEA)-1+ cells, which we have designated intestinal villous M cells. Interestingly, villous M cells are developed in various PP [or gut-associated lymphoid tissue (GALT)]-null mice, such as in utero lymphotoxin

receptor (LT

R)-Ig-treated, lymphotoxin

(LT

)-/-, tumor necrosis factor/LT

-/-, and inhibition of differentiation 2 (Id2)-/- mice. Intestinal villous M cells have been observed to take up GFP-expressing Salmonella, Yersinia, and Escherichia coli-expressing invasin, as well as gut bacterial antigen for subsequent induction of antigen-specific immune responses. Thus, the identified villous M cells could be an alternative and PP-independent gateway for the induction of antigen-specific immune responses by means of the mucosal compartment.

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^bM.H.J. and M.-N.K. contributed equally to this work.

^lTo whom correspondence should be addressed at the d address.

www.pnas.org/cgi/doi/10.1073/pnas.0400969101