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長期液性免疫記憶を支える骨髄nicheの構築とその制御

Research Project

Project/Area Number 22H00450
Research Category

Grant-in-Aid for Scientific Research (A)

Allocation TypeSingle-year Grants
Section一般
Review Section Medium-sized Section 49:Pathology, infection/immunology, and related fields
Research InstitutionOsaka University

Principal Investigator

黒崎 知博  大阪大学, 免疫学フロンティア研究センター, 招へい教授 (50178125)

Project Period (FY) 2022-04-01 – 2025-03-31
Project Status Granted (Fiscal Year 2024)
Budget Amount *help
¥42,900,000 (Direct Cost: ¥33,000,000、Indirect Cost: ¥9,900,000)
Fiscal Year 2024: ¥12,350,000 (Direct Cost: ¥9,500,000、Indirect Cost: ¥2,850,000)
Fiscal Year 2023: ¥12,350,000 (Direct Cost: ¥9,500,000、Indirect Cost: ¥2,850,000)
Fiscal Year 2022: ¥18,200,000 (Direct Cost: ¥14,000,000、Indirect Cost: ¥4,200,000)
Keywords免疫記憶 / 抗体 / 変異ウイルス / メモリーB細胞 / メモリープラズマ細胞 / Niche / 長期生存 / niche
Outline of Research at the Start

「免疫記憶」、この反応を用いた予防・治療法は、ワクチン療法である、は免疫学において解明されなければならない最重要課題の一つである。しかし、「液性免疫記憶」の場合、それを担う細胞、メモリープラズマ細胞の特徴的性質、高親和性IgG抗体を産生し長期生存する、を支えるメカニズム研究は、非常に難しい課題と考えられてきた。本研究では、メモリープラズマ細胞が、如何にしてniche構成細胞群と相互作用し、生体の中で特徴的性質(高親和性・長期生存性)を獲得するかを明らかにする。

Outline of Annual Research Achievements

獲得免疫系で最も特徴的な現象は、メモリーをもつことである。例えば、ヒトでは、麻疹ワクチン接種後、ウイルスに対するメモリープラズマ細胞(高親和性抗体産生細胞)が作られ長期生存し、できた抗体によりウイルスを迅速排除し、あたかも感染が起こらなかったように見えるわけである。よって、このメモリーを用いて人類は麻疹ウイルスの撲滅に成功してきた。しかし、「どのようなメカニズムで、高親和性メモリープラズマ細胞が長期生存するのか」という根源的問いかけがなされておらず、従って、「感染とは異なり、インフルエンザワクチンでは、なぜウイルス抗体が長期間持続せず、毎年接種しなければいけないのか」という疑問が未解決のままである。
従来の方法論では、プラズマ細胞同定は、B220-CD138+という染色法だけが可能だったので、ある時期B220-CD138+と染色されたプラズマ細胞が、いつ産生され、その後どれだけ時間経過・成熟したかの情報は全く得ることができなかった。即ち、プラズマ細胞が産生されてからの一生をトレースできていなかった。申請者らは、その弱点を克服するためstamping法を開発した。このアッセイ系を用いると、メモリープラズマ前駆細胞が産生されてから成熟するまでの重要な成熟・生存チェックポイントを明らかにすることができる。
この方法を用いて、外来性抗原の免疫で作られる抗原特異的プラズマ細胞の動態を調べた。2次リンパ節・脾臓で産生されたプラズマ細胞を見てみると、転写因子KLE2の発現に注目し、KLF2hi KLF2loと2種類の細胞亜集団が存在し、KLF2hiのプラズマ細胞だけegress receptorであるS1PRIの発現が高く血中に出ていく。その後KLF2hiプラズマ細胞は骨髄に定着して長期生存することが明らかになった。

Current Status of Research Progress
Current Status of Research Progress

1: Research has progressed more than it was originally planned.

Reason

Stamping mouseを樹立することにより初めてKLF2hi KLF2loと2種類の動態のことなるプラズマ細胞が作られているという発見につながった。

Strategy for Future Research Activity

今までIgGプラズマ細胞を中心に研究を遂行してきたが、プラズマ細胞の産生場所の違いにより動態が異なることが十分予測され、腸管パイエル板で産生されるIgAプラズマ細胞を詳細に検討してKLF2発現の違いを生じさせる原因についてさらに探索していく。

Report

(3 results)
  • 2023 Annual Research Report
  • 2022 Comments on the Screening Results   Annual Research Report
  • Research Products

    (37 results)

All 2024 2023 2022 Other

All Journal Article (11 results) (of which Int'l Joint Research: 7 results,  Peer Reviewed: 11 results,  Open Access: 9 results) Presentation (24 results) (of which Int'l Joint Research: 11 results,  Invited: 23 results) Remarks (2 results)

  • [Journal Article] STIM-mediated calcium influx regulates maintenance and selection of germinal center B cells2024

    • Author(s)
      Yutaro Yada, Masanori Matsumoto, Takeshi Inoue, Akemi Baba, Ryota Higuchi, Chie Kawai, Masashi Yanagisawa, Daisuke Kitamura, Shouichi Ohga, Tomohiro Kurosaki, Yoshihiro Baba
    • Journal Title

      Journal of Experimental Medicine

      Volume: 221 Issue: 1

    • DOI

      10.1084/jem.20222178

    • Related Report
      2023 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Regulation mechanisms of <scp>CARMA1</scp> ?Bcl10? <scp>MALT1</scp> complex assembly inferred from the analysis of <scp>TRAF6</scp> ‐deficient cells2023

    • Author(s)
      Inoue Kentaro、Yasuda Tomoharu、Baba Yoshihiro、Yamamoto Tadashi、Kurosaki Tomohiro、Shinohara Hisaaki
    • Journal Title

      Genes to Cells

      Volume: - Issue: 6 Pages: 411-421

    • DOI

      10.1111/gtc.13022

    • Related Report
      2023 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] CD62L expression marks SARS-CoV-2 memory B cell subset with preference for neutralizing epitopes2023

    • Author(s)
      Onodera T, Sax N, Sato T, Adachi Y, Kotaki R, Inoue T, Shinnakasu R, Nakagawa T, Fukushi S, Terooatea T, Yoshikawa M, Tonouchi K, Nagakura T, Moriyama S, Matsumura T, Isogawa M, Terahara K, Takano T, Sun L, Nishiyama A, Omoto S, Shinkai M, Kurosaki T, Yamashita K, Takahashi Y.
    • Journal Title

      Science Advances

      Volume: 9 Issue: 24

    • DOI

      10.1126/sciadv.adf0661

    • Related Report
      2023 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Memory B cells2023

    • Author(s)
      Inoue T, Kurosaki T.
    • Journal Title

      Nature Reviews Immunology

      Volume: 24 Issue: 1 Pages: 5-17

    • DOI

      10.1038/s41577-023-00897-3

    • Related Report
      2023 Annual Research Report
    • Peer Reviewed
  • [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

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Antibody feedback contributes to facilitating the development of Omicron-reactive memory B cells in SARS-CoV-2 mRNA vaccinees2023

    • Author(s)
      Inoue T, Shinnakasu R, Kawai C, Yamamoto H, Sakakibara S, Ono C, Itoh Y, Terooatea T, Yamashita K, Okamoto T, Hashii N, Ishii-Watabe A, Butler NS, Matsuura Y, Matsumoto H, Otsuka S, Hiraoka K, Teshima T, Murakami M, Kurosaki T.
    • Journal Title

      J Exp Med.

      Volume: 220(2) Issue: 2

    • DOI

      10.1084/jem.20221786

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] BACH2 restricts NK cell maturation and function, limiting immunity to cancer metastasis2022

    • Author(s)
      Imianowski CJ, Whiteside SK, Lozano T, Evans AC, Benson JD, Courreges CJF, Sadiyah F, Lau CM, Zandhuis ND, Grant FM, Schuijs MJ, Vardaka P, Kuo P, Soilleux EJ, Yang J, Sun JC, Kurosaki T, Okkenhaug K, Halim TYF, Roychoudhuri R.
    • Journal Title

      Journal of Experimental Medicine

      Volume: 219 Issue: 12

    • DOI

      10.1084/jem.20211476

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] BATF epigenetically and transcriptionally controls the activation program of regulatory T cells in human tumors2022

    • 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

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] The transcription factor Bach2 negatively regulates murine natural killer cell maturation and function2022

    • Author(s)
      Li S, Bern MD, Miao B, Fan C, Xing X, Inoue T, Piersma SJ, Wang T, Colonna M, Kurosaki T, Yokoyama WM.
    • Journal Title

      eLife

      Volume: 11

    • DOI

      10.7554/elife.77294

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Pyruvate enhances oral tolerance via GPR31.2022

    • Author(s)
      Liu Q, Umemoto E, Morita N, Kayama H, Baba Y, Kurosaki T, Okumura R, Takeda K.
    • Journal Title

      International Immunology

      Volume: in press Issue: 7 Pages: 343-352

    • DOI

      10.1093/intimm/dxac010

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Recycling of memory B cells between germinal center and lymph node subcapsular sinus supports affinity maturation to antigenic drift2022

    • Author(s)
      Zhang Y, Garcia-Ibanez L, Ulbricht C, Lok LSC, Pike JA, Mueller-Winkler J, Dennison TW, Ferdinand JR, Burnett CJM, Yam-Puc JC, Zhang L, Alfaro RM, Takahama Y, Ohigashi I, Brown G, Kurosaki T, Tybulewicz VLJ, Rot A, Hauser AE, Clatworthy MR, Toellner KM.
    • Journal Title

      Nature Communications

      Volume: 13 Issue: 1 Pages: 2460-2460

    • DOI

      10.1038/s41467-022-29978-y

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Presentation] Regulation of humoral memory compartments2024

    • Author(s)
      Kurosaki, T
    • Organizer
      Seminar, CBM, Spain
    • Related Report
      2023 Annual Research Report
    • Invited
  • [Presentation] 抗体長期持続性を支えるメカニズム2024

    • Author(s)
      黒崎 知博
    • Organizer
      セミナー、北海道大学
    • Related Report
      2023 Annual Research Report
    • Invited
  • [Presentation] Antibody feedback contributes to facilitating the development of Omicron-reactive memory B cells in SARS-CoV-2 mRNA vaccines2023

    • Author(s)
      Kurosaki, T.
    • Organizer
      Ravetch Alumni Meeting
    • Related Report
      2023 Annual Research Report
    • Invited
  • [Presentation] メモリーB細胞・プラズマ細胞の機能・生成メカニズム2023

    • Author(s)
      黒崎 知博
    • Organizer
      第122回日本皮膚科学会総会
    • Related Report
      2023 Annual Research Report
    • Invited
  • [Presentation] Requirement for optimal BCR signal strength in efficient positive selection of germinal center (GC) B cells2023

    • Author(s)
      Kurosaki, T.
    • Organizer
      B Cell Biology in the Context of Infectious Diseases, Autoimmunity and B Cell Cancers. Keystone Symposia
    • Related Report
      2023 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] 免疫記憶を支えるリンパ球2023

    • Author(s)
      黒崎 知博
    • Organizer
      免疫ふしぎ未来2023
    • Related Report
      2023 Annual Research Report
    • Invited
  • [Presentation] Bリンパ球・抗体を介しての免疫多様性獲得2023

    • Author(s)
      黒崎 知博
    • Organizer
      第24回 日本免疫学会サマースクール in 福岡 福岡アイランドシティフォーラム
    • Related Report
      2023 Annual Research Report
    • Invited
  • [Presentation] Bリンパ球制御によるユニヴァーサルワクチン開発2023

    • Author(s)
      黒崎 知博
    • Organizer
      「第63回 生命科学夏の学校」のワークショップ
    • Related Report
      2023 Annual Research Report
    • Invited
  • [Presentation] Fate Decision mechanism of germinal center (GC) B cell2023

    • Author(s)
      Kurosaki, T.
    • Organizer
      Finnish-Japanese immunology symposium
    • Related Report
      2023 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Regulation of plasma cell egress from secondary lymphoid tissues and its retention in bone marrow2023

    • Author(s)
      Kurosaki, T
    • Organizer
      T and B Cell Collaboration in Germinal Centers and Beyond. Keystone Symposia
    • Related Report
      2023 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] Generation mechanisms of humoral memory compartments2023

    • Author(s)
      Kurosaki, T
    • Organizer
      THE IMMUNE ALLIANCE - A GERMAN-JAPANESE COOPERATION IN IMMUNOLOGY(Web Seminar)
    • Related Report
      2023 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] 液性免疫の古くて新しい課題;抗体の多様性獲得とその維持機構2023

    • Author(s)
      黒崎 知博
    • Organizer
      KODOカンファレンス、Web開催
    • Related Report
      2023 Annual Research Report
    • Invited
  • [Presentation] 胚中心B細胞運命決定機構2023

    • Author(s)
      黒崎 知博
    • Organizer
      大学院特別講義、岡山大学
    • Related Report
      2023 Annual Research Report
    • Invited
  • [Presentation] Requirement for optimal BCR signal strength in efficient positive selection of germinal center (GC) B cells2023

    • Author(s)
      Kurosaki, T
    • Organizer
      Immunoreceptor Signaling and therapeutic Applications. Cold Spring Harbor Asia
    • Related Report
      2023 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] 免疫記憶・ワクチン開発の基盤研究2023

    • Author(s)
      黒崎 知博
    • Organizer
      2023年度持田記念学術賞記念講演
    • Related Report
      2023 Annual Research Report
    • Invited
  • [Presentation] 胚中心B細胞運命決定機構2023

    • Author(s)
      黒崎 知博
    • Organizer
      「胚中心B細胞運命決定機構」セミナー、鳥取大学
    • Related Report
      2023 Annual Research Report
    • Invited
  • [Presentation] Functional dissection of two humoral memory compartments in virus re-infection2023

    • Author(s)
      Kurosaki T
    • Organizer
      IFReC-Doherty Institute &partners Immunology Symposium
    • Related Report
      2022 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] How can diversity of memory B cells be formed?2022

    • Author(s)
      Kurosaki T
    • Organizer
      Seminar at Hokkaido University
    • Related Report
      2022 Annual Research Report
    • Invited
  • [Presentation] How diversity of memory B cell can be formed2022

    • Author(s)
      Kurosaki T
    • Organizer
      Seminar at University of Occupational and Environmental Health
    • Related Report
      2022 Annual Research Report
    • Invited
  • [Presentation] Involvement of BCR signal strength in Germinal center selection.2022

    • Author(s)
      Kurosaki T
    • Organizer
      The EMBO workshop on Germinal centers and immune niches
    • Related Report
      2022 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] Differentiation to plasma cells and their fates2022

    • Author(s)
      Kurosaki T
    • Organizer
      Dynamics of Immune Repertoires: Exploration and Translation working group “The primary B-cell immune response”
    • Related Report
      2022 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] Memory B cells; their generation and activation mechanisms2022

    • Author(s)
      Kurosaki T
    • Organizer
      EMBO Workshop Lymphocyte antigen receptor signaling
    • Related Report
      2022 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] B cell fate decisions during germinal center (GC) reactions2022

    • Author(s)
      Kurosaki T
    • Organizer
      Ravetch Alumni Meeting
    • Related Report
      2022 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] B cell fate decisions during germinal center (GC) reactions2022

    • Author(s)
      Kurosaki T
    • Organizer
      UCL Symposium
    • Related Report
      2022 Annual Research Report
    • Int'l Joint Research / Invited
  • [Remarks] http://lymph.ifrec.osaka-u.ac.jp/

    • Related Report
      2023 Annual Research Report
  • [Remarks] http://lymph.ifrec.osaka-u.ac.jp/

    • Related Report
      2022 Annual Research Report

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Published: 2022-04-19   Modified: 2024-12-25  

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