Function of Bach2 during memory B cell differentiaion

• Project/Area Number: 17K08882
• 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: Inoue Takeshi 大阪大学, 免疫学フロンティア研究センター, 特任准教授(常勤) (80466838)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000); Fiscal Year 2019: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2018: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000); Fiscal Year 2017: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: 記憶B細胞 / Bach2 / 胚中心 / 代謝 / 免疫学

Outline of Final Research Achievements

Clarifying the molecular mechanisms how memory B cells generate from the germinal center is essential for the understanding of humoral immune responses and effective vaccine design strategy, but little is known about its mechanisms. As we previously reported that Bach2 is essential for memory B cell generation, here I tried to understand how Bach2 is involved in this process. I found that the lower mTORC1 activity in proliferative germinal center B cells is favorable for efficient generation of quiescent memory B cells, and Bach2 has an important role in metabolic change during this process.

Academic Significance and Societal Importance of the Research Achievements

現在、HIVウイルス、インフルエンザウイルス、新型コロナウイルス等のウイルスに対して長期間有効で、更に変異ウイルスに対しても効果的なワクチンの開発が待望されている。このためには、記憶B細胞がどのようなメカニズムで産生されるのか、どの記憶B細胞サブセットをターゲットにしてワクチン開発をおこなえばいいのか、どの細胞系列がワクチン長期有効性に重要なのか、等の基礎的理解が不可欠である。Bach2標的遺伝子とその制御メカニズムを明らかにすることで、記憶B細胞を人為的に効率よく誘導することができれば、Bach2を標的としたワクチンや免疫疾患の創薬開発につながる可能性がある。

Research Products

• [Int'l Joint Research] The Rockefeller University(米国)
• [Int'l Joint Research] The Rockefeller University(米国)
• [Int'l Joint Research] The Rockefeller University/Washington University School of Medicine(米国)
• [Journal Article] B cell‐intrinsic MyD88 signaling controls IFN‐γ‐mediated early IgG2c class switching in mice in response to a particulate adjuvant (2019)
  • Author(s): Lee Michelle Sue Jann、Natsume‐Kitatani Yayoi、Temizoz Burcu、Fujita Yukiko、Konishi Aki、Matsuda Kyoko、Igari Yoshikatsu、Tsukui Toshihiro、Kobiyama Kouji、Kuroda Etsushi、Onishi Motoyasu、Marichal Thomas、Ise Wataru、Inoue Takeshi、Kurosaki Tomohiro、Mizuguchi Kenji、Akira Shizuo、Ishii Ken J、Coban Cevayir
  • Journal Title: European Journal of Immunology Volume: 49 Issue: 9 Pages: 1433-1440
  • DOI: 10.1002/eji.201848084
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Generation of memory B cells and their reactivation. (2018)
  • Author(s): Inoue T, Moran I, Shinnakasu R, Phan TG, Kurosaki T.
  • Journal Title: Immunological Reviews Volume: 283(1) Issue: 1 Pages: 138-149
  • DOI: 10.1111/imr.12640
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] KLRG1+ effector CD8+ T cells lose KLRG1, differentiate into all memory T cell lineages, and convey enhanced protective immunity (2018)
  • Author(s): Dietmar Herndler-Brandstetter, Harumichi Ishigame, Ryo Shinnakasu, Valerie Plajer, Carmen Stecher, Jun Zhao, Melanie Lietzenmayer, Lina Kroehling, Akiko Takumi, Kohei Kometani, Takeshi Inoue, Yuval Kluger, Susan M. Kaech, Tomohiro Kurosaki, Takaharu Okada & Richard A. Flavell
  • Journal Title: Immunity Volume: 48(4) Issue: 4 Pages: 716-729
  • DOI: 10.1016/j.immuni.2018.03.015
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] A distinct subpopulation of CD25－ T-follicular regulatory cells localizes in the germinal centers (2017)
  • Author(s): James Badger Wing, Yohko Kitagawa, Michela Locci, Hannah Hume, Christopher Tay, Takayoshi Morita, Yujiro Kidani, Kyoko Matsuda, Takeshi Inoue, Tomohiro Kurosaki, Shane Crotty, Cevayir Coban, Naganari Ohkura, and Shimon Sakaguchi
  • Journal Title: Proceedings of the National Academy of Sciences Volume: 114 Issue: 31 Pages: 6400-6400
  • DOI: 10.1073/pnas.1705551114
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] The transcription factor Foxo1 controls germinal center B cell proliferation in response to T cell help. (2017)
  • Author(s): Inoue T, Shinnakasu R, Ise W, Kawai C, Egawa T, Kurosaki T.
  • Journal Title: J. Exp. Med. Volume: 214 Issue: 4 Pages: 1181-1198
  • DOI: 10.1084/jem.20161263
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Presentation] B cell fate decision during germinal center reaction (2020)
  • Author(s): Takeshi Inoue
  • Organizer: Rising Stars in Cutting Edge Immunology Research
  • Int'l Joint Research / Invited
• [Presentation] B cell fate decision during germinal center reaction (2020)
  • Author(s): Takeshi Inoue
  • Organizer: U.S.-Japan Cooperative Medical Sciences Program (USJCMSP) 22nd International Conference on Emerging Infectious Diseases in the Pacific Rim
  • Int'l Joint Research / Invited
• [Presentation] mTORC1 and BCR signal regulate the formation of memory precursors in the germinal center (2019)
  • Author(s): Takeshi Inoue, Tomohiro Kurosaki
  • Organizer: 第48回日本免疫学会学術集会
  • Invited
• [Presentation] Germinal center-mediated memory B cell development is driven by cooperation of metabolic fitness and survival (2019)
  • Author(s): 井上 毅
  • Organizer: Keystone Symposia
  • Int'l Joint Research