Comprehensive understanding of M cells, unique intestinal epithelial cells specialized for luminal particulate antigen uptake

• Project/Area Number: 16K08836
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Immunology
• Research Institution: Osaka University
• Principal Investigator: Sato Shintaro 大阪大学, 微生物病研究所, 特任准教授(常勤) (80447333)
• Project Period (FY): 2016-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000); Fiscal Year 2018: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000); Fiscal Year 2017: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2016: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
• Keywords: 粘膜免疫 / M細胞 / Aif1 / 抗原取り込み / 腸管感染症

Outline of Final Research Achievements

We show that mouse allograft inflammatory factor 1 (Aif1) is expressed by M cells and contributes to M-cell transcytosis. FAE in Aif1－/－ mice has suppressed uptake of particles and commensal bacteria, compared with wild-type mice. Translocation of Yersinia enterocolitica, but not of Salmonella enterica serovar Typhimurium, leading to the generation of antigen-specific IgA antibodies, is also diminished in Aif1-deficient mice. Although β1 integrin, which acts as a receptor for Y. enterocolitica via invasin protein, is expressed on the apical surface membranes of M cells, its active form is rarely found in Aif1－/－ mice. These findings show that Aif1 is important for bacterial and particle transcytosis in M cells.

Academic Significance and Societal Importance of the Research Achievements

本研究成果として、M細胞の機能発現に直接関わる分子としてAif1を同定し、M細胞におけるその機能、分子メカニズムを世界に先駆けて報告した。Aif1はM細胞の外来抗原取り込み能に直接関与していることから、Aif1の機能を調節することが出来れば、食物抗原やアレルゲン、病原性微生物の侵入を一過性にコントロールすることが可能となる。したがって、Aif1をターゲットとした薬剤の開発は、効果的な経口粘膜免疫寛容の誘導や腸管感染症の予防につながるものと考えられる。

Research Products

• [Journal Article] Sox8 is essential for M cell maturation to accelerate IgA response at the early stage after weaning in mice (2019)
  • Author(s): Kimura Shunsuke、Kobayashi Nobuhide、Nakamura Yutaka、Kanaya Takashi、Takahashi Daisuke、Fujiki Ryoji、Mutoh Mami、Obata Yuuki、Iwanaga Toshihiko、Nakagawa Tomoo、Kato Naoya、Sato Shintaro、Kaisho Tsuneyasu、Ohno Hiroshi、Hase Koji
  • Journal Title: J Exp Med Volume: 216 Pages: 831-846
  • DOI: 10.1084/jem.20181604
  • Peer Reviewed / Open Access
• [Journal Article] Human Norovirus Propagation in Human Induced Pluripotent Stem Cell?Derived Intestinal Epithelial Cells (2019)
  • Author(s): Sato Shintaro、Hisaie Kota、Kurokawa Shiho、Suzuki Akio、Sakon Naomi、Uchida Yohei、Yuki Yoshikazu、Kiyono Hiroshi
  • Journal Title: Cell. Mol. Gastro. Hepatol. Volume: 7 Pages: 164-4
  • DOI: 10.1016/j.jcmgh.2018.11.001
  • Peer Reviewed / Open Access
• [Journal Article] Intravesicular Acidification Regulates Lipopolysaccharide Inflammation and Tolerance through TLR4 Trafficking. (2018)
  • Author(s): Murase M, Kawasaki T, Hakozaki R, Sueyoshi T, Putri DDP, Kitai Y, Sato S, Ikawa M, Kawai T.
  • Journal Title: The Journal of Immunology Volume: -- Pages: 2798-2808
  • DOI: 10.4049/jimmunol.1701390
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Eosinophil depletion suppresses radiation-induced small intestinal fibrosis. (2018)
  • Author(s): Takemura N, Kurashima Y, Mori Y, Okada K, Ogino T, Osawa H, Matsuno H, Aayam L, Kaneto S, Park EJ, Sato S, Matsunaga K, Tamura Y, Ouchi Y, Kumagai Y, Kobayashi D, Suzuki Y, Yoshioka Y, Nishimura J, Mori M, Ishii KJ, Rothenberg ME, Kiyono H, Akira S, Uematsu S.
  • Journal Title: Science Translational Medicine Volume: -- Pages: 0-0
  • DOI: 10.1126/scitranslmed.aan0333
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Lymphoid tissue-resident Alcaligenes LPS induces IgA production without excessive inflammatory responses via weak TLR4 agonist activity (2018)
  • Author(s): N. Shibata, J. Kunisawa, K. Hosomi, Y. Fujimoto, K. Mizote, N. Kitayama, A. Shimoyama, H. Mimuro, S. Sato, N. 5 Kishishita, K. J. Ishii, K. Fukase, and H. Kiyono
  • Journal Title: Mucosal Immunol Volume: － Pages: 693-702
  • DOI: 10.1038/mi.2017.103
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Development of immune and microbial environment is independently regulated in the mammary gland (2018)
  • Author(s): Niimi K, Usami K, Fujita Y, Abe M, Furukawa M, Suyama Y, Sakai Y, Kamioka M, Shibata N, Park EJ, Sato S, Kiyono H, Yoneyama H, Kitazawa H, Watanabe K, Nochi T, Aso H
  • Journal Title: Mucosal Immunol Volume: 印刷中 Pages: 643-653
  • DOI: 10.1038/mi.2017.90
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] A Refined Culture System for Human Induced Pluripotent Stem Cell-Derived Intestinal Epithelial Organoids. (2018)
  • Author(s): Takahashi Y, Sato S, Kurashima Y, Yamamoto T, Kurokawa S, Yuki Y, Takemura N, Uematsu S, Lai CY, Otsu M, Matsuno H, Osawa H, Mizushima T, Nishimura J, Hayashi M, Yamaguchi T, Kiyono H.
  • Journal Title: Stem Cell Reports Volume: -- Pages: 314-328
  • DOI: 10.1016/j.stemcr.2017.11.004
  • Peer Reviewed / Open Access
• [Journal Article] Reciprocal Inflammatory Signaling Between Intestinal Epithelial Cells and Adipocytes in the Absence of Immune Cells. (2017)
  • Author(s): Takahashi Y, Sato S , Kurashima Y, Lai CY, Otsu M, Hayashi M, Yamaguchi T, Kiyono H.
  • Journal Title: EBioMedicine Volume: 23 Pages: 34-45
  • DOI: 10.1016/j.ebiom.2017.07.027
  • Peer Reviewed / Open Access
• [Journal Article] Allograft inflammatory factor 1 (Aif1) is a regulator of transcytosis in M cells. (2017)
  • Author(s): Kishikawa, S., Sato, S., Kaneto, S. Uchino, S., Kohsaka, S., Nakamura, S. and Kiyono, H.
  • Journal Title: Nat Commun Volume: 8 Pages: 14509-14509
  • DOI: 10.1038/ncomms14509
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Presentation] Identification and Elucidation of Novel M-cell specific Molecules for Its Function and Differentiation (2018)
  • Author(s): Shintaro Sato and Hiroshi Kiyono
  • Organizer: 第22回腸内細菌学会
  • Int'l Joint Research / Invited
• [Presentation] 抗原取り込み特化細胞、M細胞におけるAllograft inflammatory factor1 (Aif1)の役割 (2017)
  • Author(s): 佐藤慎太郎
  • Organizer: 日本薬学会第137回年会
  • Place of Presentation: 仙台
  • Year and Date: 2017-03-25
• [Presentation] 腸管免疫抗原取り込み機能分子Aif1の同定と解析 (2017)
  • Author(s): 佐藤慎太郎
  • Organizer: 第41回日本リンパ学会総会
  • Invited
• [Presentation] Allograft inflammatory factor 1 (Aif1) is a regulator of transcytosis in M cells. (2017)
  • Author(s): Shintaro Sato
  • Organizer: 18th International Congress of Mucosal Immunology
  • Int'l Joint Research
• [Remarks]
  • URL: http://www.biken.osaka-u.ac.jp/lab/mucosal/
• [Remarks] 粘膜ワクチン開発に結びつく、経粘膜抗原取り込みに直接関わる分子を同定
  • URL: http://resou.osaka-u.ac.jp/ja/research/2017/20170222_2
• [Patent(Industrial Property Rights)] ヒトノロウイルスの増殖 (2018)
  • Inventor(s): 佐藤 慎太郎、幸 義和、清野 宏
  • Industrial Property Rights Holder: 一般財団法人阪大微生物病研究会、国立大学法人東京大学
  • Industrial Property Rights Type: 特許
  • Filing Date: 2018