Differentiation and function of M cells, a unique intestinal epithelial cell subset for untigen uptake

• Project/Area Number: 16H05207
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Immunology
• Research Institution: Institute of Physical and Chemical Research
• Principal Investigator: Ohno Hiroshi 国立研究開発法人理化学研究所, 生命医科学研究センター, チームリーダー (50233226)
• Co-Investigator(Kenkyū-buntansha): 金谷 高史 国立研究開発法人理化学研究所, 生命医科学研究センター, 上級研究員 (20553829)
• Project Period (FY): 2016-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥18,200,000 (Direct Cost: ¥14,000,000、Indirect Cost: ¥4,200,000); Fiscal Year 2018: ¥3,120,000 (Direct Cost: ¥2,400,000、Indirect Cost: ¥720,000); Fiscal Year 2017: ¥2,340,000 (Direct Cost: ¥1,800,000、Indirect Cost: ¥540,000); Fiscal Year 2016: ¥12,740,000 (Direct Cost: ¥9,800,000、Indirect Cost: ¥2,940,000)
• Keywords: 腸管免疫系 / 腸管関連リンパ組織 / M細胞 / 濾胞関連上皮 / RANKL / NF-kB / IL-22 / 食物抗原 / Spi-B / IL-22BP / 免疫学 / Ｍ細胞 / 細菌 / GALT / 濾胞関連上皮（FAE） / NFkB / 遺伝子欠損マウス / RANK / 抗菌ペプチド

Outline of Final Research Achievements

We have found that both NFkB canonical and noncanonical pathways are required, and that the transcription factor SpiB is necessary but not sufficient, for M-cell differentiation .
We found that M cell-specific surface molecule Umod acts as an uptake receptor for Lactobacillus acidophilus expressing SlpA. We also established the monolayer culture of enteroids with M-cell induction.
We have established “antigen-free” mice colony and found that fecal IgA was profoundly decreased in these mice, concomitant with marked reduction in the number of Pyer’s patch B cells and germinal center formation.

Academic Significance and Societal Importance of the Research Achievements

本研究は、Ｍ細胞の分化や機能の基礎研究であるが、その成果はM細胞を介する経粘膜感染症・食物アレルギーの効果的なワクチン送達法の開発といった医学研究・応用研究へと発展する可能性がある。したがって最終的には、Ｍ細胞を標的とする新たな粘膜ワクチン開発や、食物アレルギーに対する特異的経口免疫寛容誘導などの臨床応用へと繋がり、国民の健康にも貢献できると考えられることから、医療経済的、社会的にも意義深いと考える。

Research Products

• [Int'l Joint Research] Emory University/New York University(米国)
• [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: The Journal of Experimental Medicine Volume: 216 Issue: 4 Pages: 831-846
  • DOI: 10.1084/jem.20181604
  • Peer Reviewed / Open Access
• [Journal Article] Development of intestinal M cells and follicle-associated epithelium is regulated by TRAF6-mediated NF-κB signaling. (2018)
  • Author(s): Kanaya T, Sakakibara S, Jinnohara T, Hachisuka M, Tachibana N, Hidano S, Kobayashi T, Kimura S, Iwanaga T, Nakagawa T, Katsuno T, Kato N, Akiyama T, Sato T, Williams IR, Ohno H.
  • Journal Title: J Exp Med. Volume: 5;215(2) Issue: 2 Pages: 501-519
  • DOI: 10.1084/jem.20160659
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] NALT M cells are important for immune induction for the common mucosal immune system. (2017)
  • Author(s): Date Y, Ebisawa M, Fukuda S, Shima H, Obata Y, Takahashi D, Kato T, Hanazato M, Nakato G, Williams IR, Hase K, Ohno H.
  • Journal Title: Int. Immunol. Volume: 29 Issue: 10 Pages: 471-478
  • DOI: 10.1093/intimm/dxx064
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Uromodulin-SlpA binding dictates Lactobacillus acidophilus uptake by intestinal epithelial M cells. (2017)
  • Author(s): Yanagihara S, Kanaya T, Fukuda S, Nakato G, Hanazato M, Wu XR, Yamamoto N, Ohno H.
  • Journal Title: Int. Immunol. Volume: 29 Issue: 8 Pages: 357-363
  • DOI: 10.1093/intimm/dxx043
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] IL-22BP dictates characteristics of Peyer's patch follicle-associated epithelium for antigen uptake. (2017)
  • Author(s): Jinnohara T, Kanaya T, Hase K, Sakakibara S, Kato T, Tachibana N, Sasaki T, Hashimoto Y, Sato T, Watarai H, Kunisawa J, Shibata N, Williams I, Kiyono H, and Ohno H.
  • Journal Title: J. Exp. Med. Volume: 214 Issue: 6 Pages: 1607-1618
  • DOI: 10.1084/jem.20160770
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Distinct Roles for the N- and C-terminal Regions of M-Sec in Plasma Membrane Deformation during Tunneling Nanotube Formation. (2016)
  • Author(s): Kimura S, Yamashita M, Yamakami-Kimura M, Sato Y, Yamagata A, Kobashigawa Y, Inagaki F, Amada T, Hase K, Iwanaga T, Ohno H, Fukai S.
  • Journal Title: Scientific Reports Volume: 6 Issue: 1 Pages: 33548-33548
  • DOI: 10.1038/srep33548
  • NAID: 120005855947
  • Peer Reviewed / Open Access
• [Journal Article] High-affinity monoclonal IgA regulates gut microbiota and prevents colitis in mice. (2016)
  • Author(s): Okai S, Usui F, Yokota S, Hori-I Y, Hasegawa M, Nakamura T, Kurosawa M, Okada S, Yamamoto K, Nishiyama E, Mori H, Yamada T, Kurokawa K, Matsumoto S, Nanno M, Naito T, Watanabe Y, Kato T, Miyauchi E, Ohno H, Shinkura R.
  • Journal Title: Nature Microbiology Volume: 1 Issue: 9 Pages: 16103-16103
  • DOI: 10.1038/nmicrobiol.2016.103
  • NAID: 120005818448
  • Peer Reviewed / Open Access
• [Journal Article] Epithelium-Intrinsic MicroRNAs Contribute to Mucosal Immune Homeostasis by Promoting M-Cell Maturation. (2016)
  • Author(s): Nakato G, Hase K, Sato T, Kimura S, Sakakibara S, Sugiyama M, Obata Y,Hanazato M, Iwanaga T, Ohno H.
  • Journal Title: PLoS One Volume: 11 Issue: 3 Pages: e0150379-e0150379
  • DOI: 10.1371/journal.pone.0150379
  • Peer Reviewed / Open Access
• [Presentation] 腸管免疫を発動するM細胞の分化機構に関する研究 (2018)
  • Author(s): 金谷高史
  • Organizer: 第47回日本免疫学会学術集会
• [Presentation] Characteristics of M cells and follicle-associated epithelium (2017)
  • Author(s): Ohno, H., Kanaya, T.
  • Organizer: 第46回日本免疫学会学術集会
  • Invited
• [Presentation] IL-22 binding protein (IL-22BP) regulates the properties of follicleassociated epithelium (FAE) to facilitate antigen uptake into Peyer's patches (2017)
  • Author(s): Kanayak T., Jinnohara, T., Hase, K., Sasaki, T., Watarai, H., Shibata, N., Kuniswa, J., Kiyono, H., Ohno, H.
  • Organizer: 第46回日本免疫学会学術集会
• [Presentation] Lactobacillus acidophilus L-92株の小腸パイエル板の M細胞からの取り込みに関与する生体分子の探索 (2017)
  • Author(s): 柳原 沙恵, 金谷 高史, 弘田 辰彦, 山本 直之, 大野 博司
  • Organizer: 第13回日本食品免疫学会学術大会
• [Presentation] The function of M cells in host-microbe interaction (2017)
  • Author(s): Ohno, H
  • Organizer: Symposium 207 Gut Microbiome and Mucosal or Systemic Dysfunction Mechanisms, Clinical Manifenstations and Intervention
  • Invited
• [Presentation] Lactobacillus acidophilus L-92株の表層蛋白質が小腸パイエル板のM細胞からの取り込みに与える影響 (2016)
  • Author(s): 柳原沙恵、福田真嗣、金谷高史、弘田辰彦、山本直之、大野博司
  • Organizer: 日本乳酸菌学会2016年度大会
  • Place of Presentation: 北里大学白金キャンパスコンベンションホール(東京都・港区）
  • Year and Date: 2016-07-09
• [Presentation] 腸管免疫とＭ細胞 (2016)
  • Author(s): 大野博司
  • Organizer: 第40 回日本リンパ学会総会
  • Place of Presentation: 東京大学伊藤国際学術研究センター（東京都・文京区）
  • Year and Date: 2016-06-24
  • Invited
• [Remarks] 理化学研究所生命医科学研究センター粘膜システム研究チーム
  • URL: http://www.riken.jp/research/labs/ims/intest_ecosys/
• [Remarks] Laboratory for Intestinal Ecosystem, RIKEN IMS h
  • URL: http://www.riken.jp/en/research/labs/ims/intest_ecosys/
• [Remarks] 理化学研究所生命医科学研究センター粘膜システム研究チーム
  • URL: http://leib.rcai.riken.jp/riken/index.html
• [Remarks] Laboratory for Intestinal Ecosystem, RIKEN IMS
  • URL: http://www.riken.jp/en/research/labs/ims/intest_ecosys/
• [Remarks]
  • URL: http://www.riken.jp/research/labs/ims/intest_ecosys/
• [Remarks]
  • URL: http://leib.rcai.riken.jp/riken/index.html