Mechanisms underlying long-term survival and immune-modulatory function of plasma cells

• Project/Area Number: 20H03503
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Review Section: Basic Section 49070:Immunology-related
• Research Institution: Osaka University
• Principal Investigator: ISE Wataru 大阪大学, 感染症総合教育研究拠点, 教授 (70323483)
• Project Period (FY): 2020-04-01 – 2023-03-31
• Project Status: Completed (Fiscal Year 2022)
• Budget Amount: ¥17,680,000 (Direct Cost: ¥13,600,000、Indirect Cost: ¥4,080,000); Fiscal Year 2022: ¥5,980,000 (Direct Cost: ¥4,600,000、Indirect Cost: ¥1,380,000); Fiscal Year 2021: ¥5,590,000 (Direct Cost: ¥4,300,000、Indirect Cost: ¥1,290,000); Fiscal Year 2020: ¥6,110,000 (Direct Cost: ¥4,700,000、Indirect Cost: ¥1,410,000)
• Keywords: 抗体 / プラズマ細胞 / 長期生存 / インテグリン / 生存

Outline of Research at the Start

プラズマ細胞から産生される抗体はウイルスや細菌の排除に必要不可欠である。プラズマ細胞の一部は骨髄などで長期に渡って生存し、抗体を産生し続けることから、プラズマ細胞の生存を支える分子基盤を明らかにすることはワクチン開発やアレルギー、自己免疫疾患の治療法開発にも重要である。申請者は長期生存プラズマ細胞を特異的に蛍光ラベルし、追跡・分離できる新たな実験系の樹立に成功した。本研究ではこの実験系を用いて、長期生存プラズマ細胞のマーカーの同定、生存制御機構の解明、そして抗体クラス特異的生存機構や局在の生理的意義の解明を試みる。

Outline of Final Research Achievements

We analyzed long-term survival of plasma cells in bone marrow, spleen, or gut by using plasma cell fate mapping system. We found that plasma cells survive in bone marrow better than in other tissues with isotype-dependent half-lives. Furthermore, we demonstrated that long-lived plasma cells are B220loMHC-IIlo and are immobilized in the BM environment. Unexpectedly, there was no significant difference in the longevity between pre-GC and post-GC plasma cells. Finally, we analyzed molecular mechanisms by which plasma cells generated in lymphoid tissues migrate to bone marrow and found that the transcription factor KLF2 is required for integrin beta 7 positive plasma cells to migrate to bone marrow.

Academic Significance and Societal Importance of the Research Achievements

プラズマ細胞の長期生存を支える分子機構を解明することは、ワクチン開発のみならず、アレルギーや自己免疫疾患の治療法開発にも重要である。本研究ではプラズマ細胞の生存ニッチとしての骨髄の重要性を確認すると同時に、長寿命プラズマ細胞の骨髄移動の分子メカニズムを初めて明らかにした。また長寿命プラズマ細胞を識別可能なマーカーの同定にも成功した。本研究の成果は、抗体産生応答の持続性に優れたワクチン開発に大きく貢献するものである。

Research Products

• [Journal Article] Progressive differentiation toward the long-lived plasma cell compartment in the bone marrow. (2023)
  • Author(s): Koike T, Fujii K, Kometani K, Butler NS, Funakoshi K, Yari S, Kikuta J, Ishii M, Kurosaki T, Ise W
  • Journal Title: Journal of Experimental Medicine Volume: 220 Issue: 2 Pages: 2-2
  • DOI: 10.1084/jem.20221717
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] BATF epigenetically and transcriptionally controls the activation program of regulatory T cells in human tumors (2022)
  • Author(s): Itahashi Kota、Irie Takuma、Yuda Junichiro、Kumagai Shogo、Tanegashima Tokiyoshi、Lin Yi-Tzu、Watanabe Sho、Goto Yasushi、Suzuki Jun、Aokage Keiju、Tsuboi Masahiro、Minami Yosuke、Ishii Genichiro、Ohe Yuichiro、Ise Wataru、Kurosaki Tomohiro、Suzuki Yutaka、Koyama Shohei、Nishikawa Hiroyoshi
  • Journal Title: Science Immunology Volume: 7 Issue: 76 Pages: 1-20
  • DOI: 10.1126/sciimmunol.abk0957
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Batf-mediated epigenetic control of effector CD8 ⁺ T cell differentiation (2022)
  • Author(s): Tsao Hsiao-Wei、Kaminski James、Kurachi Makoto、Barnitz R. Anthony、DiIorio Michael A.、LaFleur Martin W.、Ise Wataru、Kurosaki Tomohiro、Wherry E. John、Haining W. Nicholas、Yosef Nir
  • Journal Title: Science Immunology Volume: 7 Issue: 68
  • DOI: 10.1126/sciimmunol.abi4919
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Plasma cell generation during T-cell-dependent immune responses (2021)
  • Author(s): Ise Wataru、Kurosaki Tomohiro
  • Journal Title: International Immunology Volume: 33 Issue: 12 Pages: 797-801
  • DOI: 10.1093/intimm/dxab071
• [Journal Article] Silencing and activating anergic B cells (2021)
  • Author(s): Shinya Tanaka, Wataru Ise, Yoshihiro Baba, Tomohiro Kurosaki
  • Journal Title: Immunological reviews Volume: 307 Issue: 1 Pages: 43-52
  • DOI: 10.1111/imr.13053
  • Peer Reviewed
• [Journal Article] B cell-intrinsic TBK1 is essential for germinal center formation during infection and vaccination in mice (2021)
  • Author(s): Lee MSL, Inoue T, Ise W, Matsuo-Dapaah J, Wing JB, Temizoz B, Kobiyama K, Hayashi T, Patil A, Sakaguchi S, Simon AK, Bezbradica JS, Nagatoishi S, Tsumoto K, Inoue J, Akira S, Kurosaki T, Ishii KJ, Coban C
  • Journal Title: Journal of Experimental Medicine Volume: 219 Issue: 2
  • DOI: 10.1084/jem.20211336
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Tet2 and Tet3 in B cells are required to repress CD86 and prevent autoimmunity (2020)
  • Author(s): Tanaka, S. Ise, W. Inoue, T. Ito, A. Ono, C. Shima, Y. Sakakibara, S. Nakayama, M. Fujii, K. Miura, I. Sharif, J. Koseki, H. Koni, P. A. Raman, I. Li, Q. Z. Kubo, M. Fujiki, K. Nakato, R. Shirahige, K. Araki, H. Miura, F. Ito, T. Kawakami, E. Baba, Y. Kurosaki, T.
  • Journal Title: Nature Immunology Volume: 21 Issue: 8 Pages: 950-961
  • DOI: 10.1038/s41590-020-0700-y
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Tet DNA demethylase is required for plasma cell differentiation by controlling expression levels of IRF4 (2020)
  • Author(s): Fujii, K. Tanaka, S. Hasegawa, T. Narazaki, M. Kumanogoh, A. Koseki, H. Kurosaki, T. Ise, W.
  • Journal Title: International Immunology Volume: 32 Issue: 10 Pages: 683-690
  • DOI: 10.1093/intimm/dxaa042
  • Peer Reviewed / Open Access
• [Presentation] 長寿命プラズマ細胞の分化と生存の制御 (2023)
  • Author(s): 伊勢 渉
  • Organizer: 第7回日本骨免疫学会 冬期学術集会
  • Invited
• [Presentation] B細胞に発現するTet2/Tet3による全身性自己免疫寛容の制御 (2021)
  • Author(s): 伊勢渉
  • Organizer: 第65回日本リウマチ学会総会・学術集会
  • Invited
• [Book] 食品免疫学事典 (2021)
  • Author(s): 日本食品免疫学会
  • Total Pages: 492
  • Publisher: 朝倉書店
  • ISBN: 9784254431261