Elucidation of induction and maintenance mechanism of universal cross reactive B cells against influenza virus

• Project/Area Number: 17K08856
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Virology
• Research Institution: Osaka University
• Principal Investigator: Shinnakasu Ryo 大阪大学, 免疫学フロンティア研究センター, 特任助教(常勤) (00451758)
• 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: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2018: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2017: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
• Keywords: 感染防御・制御 / 免疫 / メモリーB細胞 / 抗体 / B細胞 / ウイルス

Outline of Final Research Achievements

In this research , I addressed the question "why Stem-specific (universal cross reactive) memory B cells can be rarely detected in the body. For this question I clarified three things as below. (1) Stem-specific memory B cells have low in-vivo maintenance ability. (2) Stem-specific B cells are easily activated in an environment lacking Treg cells. (3) Endogenous T-bet does not affect induction of stem-specific memory B cells. From the above results, it was speculated that the number of stem-specific memory B cell progenitor cells was small due to the anergy state by autoantigen reactivity. Currently, detailed analysis of reactivity of cloned stem-specific BCR to self-antigen is underway.

Academic Significance and Societal Importance of the Research Achievements

これまでインフルエンザHA Stem部位に対する万能抗体誘導能を保持するメモリーB細胞を持っているヒトが稀に存在し、パンデミックな感染に於いても抵抗性を示すことが示されてきた。ただ、ヒト材料を用いた研究ではこの細胞の誘導機序など根源的課題へのアプローチには限界があった。本研究課題で得られる結果は、これまで誰も解明できていない Stem部位特異的メモリー細胞誘導・維持機構を細胞レベル・分子レベルで明らかにするという基礎的理解として非常に価値の高いものであり、さらに、本研究により得られた知見は、今後効果的な抗インフルエンザ万能ワクチンが開発されていく上で世の中に貢献できるものと考えられる。

Research Products

• [Journal Article] Exposure of an occluded hemagglutinin epitope drives selection of a class of cross-protective influenza antibodies (2019)
  • Author(s): Adachi Yu、Tonouchi Keisuke、Nithichanon Arnone、Kuraoka Masayuki、Watanabe Akiko、Shinnakasu Ryo、Asanuma Hideki、Ainai Akira、Ohmi Yusuke、Yamamoto Takuya、Ishii Ken J.、Hasegawa Hideki、Takeyama Haruko、Lertmemongkolchai Ganjana、Kurosaki Tomohiro、Ato Manabu、Kelsoe Garnett、Takahashi Yoshimasa
  • Journal Title: Nature Communications Volume: 10 Issue: 1 Pages: 1-13
  • DOI: 10.1038/s41467-019-11821-6
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Requirement for memory B-cell activation in protection from heterologous influenza virus reinfection (2019)
  • Author(s): Leach Sarah、Shinnakasu Ryo、Adachi Yu、Momota Masatoshi、Makino-Okamura Chieko、Yamamoto Takuya、Ishii Ken J、Fukuyama Hidehiro、Takahashi Yoshimasa、Kurosaki Tomohiro
  • Journal Title: International Immunology Volume: 31 Issue: 12 Pages: 771-779
  • DOI: 10.1093/intimm/dxz049
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Functional clustering of B cell receptors using sequence and structural features (2019)
  • Author(s): Xu Zichang、Li Songling、Rozewicki John、Yamashita Kazuo、Teraguchi Shunsuke、Inoue Takeshi、Shinnakasu Ryo、Leach Sarah、Kurosaki Tomohiro、Standley Daron M.
  • Journal Title: Molecular Systems Design & Engineering Volume: 4 Issue: 4 Pages: 769-778
  • DOI: 10.1039/c9me00021f
  • 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] 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] 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
• [Journal Article] Regulation of memory B and plasma cell differentiation. (2017)
  • Author(s): Shinnakasu R, Kurosaki T.
  • Journal Title: Curr. Opin. Immunol. Volume: 45 Pages: 126-131
  • DOI: 10.1016/j.coi.2017.03.003
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant