Molecular mechanisms underlying selection and maintenance of high affinity plasma cells

• Project/Area Number: 17K08883
• 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: Ise Wataru 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) (70323483)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000); Fiscal Year 2019: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2018: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2017: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: 抗体 / プラズマ細胞 / 胚中心 / 転写因子 / B細胞 / DNAメチル化 / Tet / IRF4 / 免疫学

Outline of Final Research Achievements

1) We identified plasma cell precursors (Bcl6loIRF4hiCD69hi cells) in germinal center (GC). The generation of these cells requires strong help from T cells via CD40 and sustained interaction with T cells. Fate mapping of GC B cells revealed that in contrast to memory B cells, plasma cells are generated from early to late GCs continuously.
2) We demonstrated that DNA demethylase Tet2 and Tet3 are required for plasma cell generation. Tet2/3-deficient B cells were not able to express high IRF4, which is essential for plasma cell generation. We found the CpG sites in Irf4 locus that are demethylated specifically in plasma cells in Tet2/3-dependent manner. These results suggest that DNA demethylation in these sites are required for high IRF4 expression and subsequent plasma cell generation.

Academic Significance and Societal Importance of the Research Achievements

抗体分子は生体に侵入してくるウイルスなどの外来異物を排除するのに必要不可欠な分子である。中でも高親和性の抗体はウイルスなどの中和活性が高く、高親和性抗体をいかに誘導するかがワクチンの成否を握ると考えられている。しかし高親和性抗体を生み出す仕組みは理解されていなかった。本研究では、高親和性抗体が生み出される場である胚中心におけるB細胞・プラズマ細胞の選択機構を明らかにすることができた。またエピジェネティック変化がプラズマ細胞分化を制御する機構も明らかにできた。本研究で得られた成果は効率の良いワクチン開発に重要な知見を与えるものである。

Research Products

• [Journal Article] Plasma Cell Differentiation (2020)
  • Author(s): Wataru Ise and Tomohiro Kurosaki
  • Journal Title: Adv. Exp. Med. Biol. Volume: 1254 Pages: 63-74
  • DOI: 10.1007/978-981-15-3532-1_6
  • ISBN: 9789811535314, 9789811535321
  • Peer Reviewed
• [Journal Article] Plasma cell differentiation during the germinal center reaction (2019)
  • Author(s): Ise Wataru、Kurosaki Tomohiro
  • Journal Title: Immunological Reviews Volume: 288 Issue: 1 Pages: 64-74
  • DOI: 10.1111/imr.12751
  • Peer Reviewed
• [Journal Article] T Follicular Helper Cell-Germinal Center B Cell Interaction Strength Regulates Entry into Plasma Cell or Recycling Germinal Center Cell Fate (2018)
  • Author(s): Ise Wataru、Fujii Kentaro、Shiroguchi Katsuyuki、Ito Ayako、Kometani Kohei、Takeda Kiyoshi、Kawakami Eiryo、Yamashita Kazuo、Suzuki Kazuhiro、Okada Takaharu、Kurosaki Tomohiro
  • Journal Title: Immunity Volume: 48 Issue: 4 Pages: 702-715
  • DOI: 10.1016/j.immuni.2018.03.027
  • Peer Reviewed / Open Access
• [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] Regulation of plasma cell differentiation from germinal center (2019)
  • Author(s): Wataru Ise
  • Organizer: 日本免疫学会
  • Invited
• [Presentation] The heightened T-B interaction associates with plasma-prone germinal center B cells (2017)
  • Author(s): 伊勢 渉
  • Organizer: 免疫学会
• [Presentation] 液性記憶免疫応答を担うB細胞の分化とその選択機構 (2017)
  • Author(s): 伊勢 渉
  • Organizer: 日本食品免疫学会
  • Invited