メモリーB細胞の形成と維持を支える内的・外的メカニズム

2016 Fiscal Year Annual Research Report

• Project/Area Number: 26221306
• Research Institution: Osaka 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, 特任教授(常勤) (50178125)
• Co-Investigator(Kenkyū-buntansha): 福山 英啓 国立研究開発法人理化学研究所, 統合生命医科学研究センター, 上級研究員 (70303956)
• Project Period (FY): 2014-05-30 – 2019-03-31
• Keywords: メモリーB細胞 / 胚中心B細胞 / プラズマ細胞 / T細胞ヘルプ / BCRシグナル / CD40シグナル

Outline of Annual Research Achievements

私たちは既に、胚中心(GC)の中で、GC B細胞はT細胞から弱いシグナルを受けると、メモリーB細胞に分化することを明らかにした。本年度は、それでは、強いシグナルを受けると、GC B細胞はどのような運命決定をするかを検索した。GC B細胞の細胞亜集団の単離・解析、BCR, T 細胞ヘルプ欠損マウスを用いて、以下の成果を得た。
1)Bcl6レポーターマウスを用いて、GC B細胞を細分化すると、Bcl6loIRF4hi という亜集団が存在し、この集団がプラズマ細胞へ分化する、直前の前駆細胞であることを、遺伝子発現パターン・BCRレパトアーの解析を用いて明らかにした。2)Bcl6loIRF4hi亜集団は、他の細胞亜集団に比べて、BCR, CD40シグナルを非常に強く受けていることがRNA発現パターンより、示唆された。3)事実BCRシグナル、CD40シグナルを減弱する変異GC B細胞では、いずれもBcl6loIRF4hiの細胞亜集団の産生が顕著に減弱していた。4)Foxo1遺伝子のpre-GC, GC phase特異的な欠損をおこなうと、pre-GCではFoxo1遺伝子欠損さすことにより、抗原特異的B細胞の、より過剰な増殖が見られた。逆にGC phaseではGC細胞の増殖phaseであるDZ GC B細胞が観察されず、又, それによりGC B細胞全体の増殖が低下した。
1)2)3)の結果は、非常に強いT細胞からのシグナルを受けるとGC B細胞は転写因子IRF4が上昇し、一方Bcl6の発現減弱が生じ、プラズマ細胞への分化が促進されると同時に、GCプログラムからの離脱が生じ、GCから出ていくようになる、ことを強く示している。

Current Status of Research Progress

2: Research has progressed on the whole more than it was originally planned.

Reason

予測以上に早く、進展しているパート(GC B細胞の分化メカニズム)と、やや遅れているパート(メモリーB細胞の生存メカニズム)が混在している。しかしながら、メモリーB細胞生存メカニズムを明らかにする、マウスも樹立しつつある。全体的には順調に進展している。

Strategy for Future Research Activity

今までの、やや遅れている面は一気に進め遅れを挽回するよう努める。又、予測以上に先行しているパートは、更にその次の重要な課題も明確になっていると同時に、必要な実験材料も樹立しているので、常に国際的にリードを保つべく進展さす。

Research Products

• [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 Pages: 1181-1198
  • DOI: 10.1084/jem.20161263.
  • Peer Reviewed / Open Access
• [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.
  • Open Access
• [Journal Article] BACH transcription factors in innate and adaptive immunity (2017)
  • Author(s): Igarashi K, Kurosaki T, Roychoudhuri R.
  • Journal Title: Nat. Rev. Immunol. Volume: 印刷中 Pages: 印刷中
  • DOI: 10.1038/nri.2017.26
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Sialylation converts arthritogenic IgG into inhibitors of collagen-induced arthritis. (2016)
  • Author(s): Ohmi, Y., Ise, W., Harazono, A., Takakura, D., Fukuyama, H., Baba, Y., Narazaki, M., Shoda, H., Takahashi, N., Ohkawa, Y., Ji, S., Sugiyama, F., Fujio, K., Kumanogoh, A., Yamamoto, K., Kawasaki, N., Kurosaki, T., Takahashi, Y., Furukawa, K.
  • Journal Title: Nat. Commun. Volume: 7 Pages: 11205
  • DOI: 10.1038/ncomms11205
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Whole-Virion Influenza Vaccine Recalls an Early Burst of High-Affinity Memory B Cell Response through TLR Signaling. (2016)
  • Author(s): Onodera T, Hosono A, Odagiri T, Tashiro M, Kaminogawa S, Okuno Y, Kurosaki T, Ato M, Kobayashi K, Takahashi Y.
  • Journal Title: J. Immunol. Volume: 196 Pages: 4172-84
  • DOI: 10.4049/jimmunol.1600046.
  • Peer Reviewed / Open Access
• [Journal Article] Regulated selection of germinal center cells into the memory B cell compartment. (2016)
  • Author(s): Shinnakasu, R., Inoue, T., Kometani, K., Moriyama, S., Adachi, Y., Nakayama, M., Takahashi, Y., Fukuyama, H., Okada, T.,Kurosaki,T.
  • Journal Title: Nat. Immunol. Volume: 17 Pages: 861-9
  • DOI: 10.1038/ni.3460
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Bach2-Batf interactions control Th2-type immune response by regulating the IL-4 amplification loop. (2016)
  • Author(s): Kuwahara M, Ise W, Ochi M, Suzuki J, Kometani K, Maruyama S, Izumoto M, Matsumoto A, Takemori N, Takemori A, Shinoda K, Nakayama T, Ohara O, Yasukawa M, Sawasaki T, Kurosaki T, Yamashita M.
  • Journal Title: Nat. Commun. Volume: 7 Pages: 12596
  • DOI: 10.1038/ncomms12596.
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Protein kinase D regulates positive selection of CD4+ thymocytes through phosphorylation of SHP-1. (2016)
  • Author(s): Ishikawa E, Kosako H, Yasuda T, Ohmuraya M, Araki K, Kurosaki T, Saito T, Yamasaki S.
  • Journal Title: Nat. Commun. Volume: 7 Pages: 12756
  • DOI: 10.1038/ncomms12756
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Conversion of T cells to B cells by inactivation of polycomb-mediated epigenetic suppression of the B-lineage program. (2016)
  • Author(s): Ikawa T, Masuda K, Endo TA, Endo M, Isono K, Koseki Y, Nakagawa R, Kometani K, Takano J, Agata Y, Katsura Y, Kurosaki T, Vidal M, Koseki H, Kawamoto H.
  • Journal Title: Genes. Dev. Volume: 30 Pages: 2475-2485
  • DOI: 10.1101/gad.290593.116
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Inhaled Fine Particles Induce Alveolar Macrophage Death and Interleukin-1α Release to Promote Inducible Bronchus-Associated Lymphoid Tissue Formation. (2016)
  • Author(s): Kuroda E, Ozasa K, Temizoz B, Ohata K, Koo CX, Kanuma T, Kusakabe T, Kobari S, Horie M, Morimoto Y, Nakajima S, Kabashima K, Ziegler SF, Iwakura Y, Ise W, Kurosaki T, Nagatake T, Kunisawa J, Takemura N, Uematsu S, Hayashi M, Aoshi T, Kobiyama K, Coban C, Ishii KJ.
  • Journal Title: Immunity Volume: 45 Pages: 1299-1310
  • DOI: 10.1016/j.immuni.2016.11.010.
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Presentation] Selection of germinal-center B cells into memory B cell or plasma cell Compartment (2017)
  • Author(s): Kurosaki, T.
  • Organizer: The 6th NIF Winter School on Advanced Immunology
  • Place of Presentation: Singapore
  • Year and Date: 2017-01-22 – 2017-01-26
  • Invited
• [Presentation] Selection mechanisms of germinal center B cells into the memory B cell compartment (2016)
  • Author(s): Shinnakasu, R.
  • Organizer: 45th Annual Meeting of the Japanese Society for Immunology.
  • Place of Presentation: 沖縄コンベンションセンター、沖縄
  • Year and Date: 2016-12-05 – 2016-12-07
  • Invited
• [Presentation] Fate decisions of germinal center B cells into the memory B cell or plasma cell compartment (2016)
  • Author(s): Kurosaki, T.
  • Organizer: 4th Antibody Symposium
  • Place of Presentation: Singapore
  • Year and Date: 2016-11-14
  • Invited
• [Presentation] Fate decisions of germinal center B cells into the memory B cell or plasma cell compartment (2016)
  • Author(s): Kurosaki, T.
  • Organizer: The International Symposium for Advanced Immunology Commemorating the 10th anniversary of IFReC and the 77th anniversary of Prof. Tadamitsu Kishimoto's birth
  • Place of Presentation: Osaka International Convention Center, Osaka, Japan
  • Year and Date: 2016-11-01 – 2016-11-02
  • Int'l Joint Research / Invited
• [Presentation] Overview of germinal center immunity (2016)
  • Author(s): Kurosaki, T.
  • Organizer: The 13th International Workshop on Autoantibodies and Autoimmunity (IWAA2016)
  • Place of Presentation: The Westin Miyako Kyoto, Kyoto, Japan
  • Year and Date: 2016-10-11 – 2016-10-13
  • Int'l Joint Research / Invited
• [Presentation] Memory B cell generation mechanisms (2016)
  • Author(s): Kurosaki, T.
  • Organizer: Annual program of monthly lectures
  • Place of Presentation: Madrid, Spain
  • Year and Date: 2016-09-08
  • Invited
• [Presentation] Transcriptional regulation in memory B cell development (2016)
  • Author(s): Kurosaki, T.
  • Organizer: EMBO conference “Lymphocyte Antigen Receptor Signaling”
  • Place of Presentation: Siena, Italy
  • Year and Date: 2016-09-03 – 2016-09-07
  • Int'l Joint Research / Invited
• [Presentation] Instructive selection of germinal center B cells into the memory compartment (2016)
  • Author(s): Kurosaki, T.
  • Organizer: International congress of Immunology 2016
  • Place of Presentation: Melbourne, Australia
  • Year and Date: 2016-08-21 – 2016-08-26
  • Int'l Joint Research / Invited
• [Presentation] Instructive selection of germinal center B cells into the memory compartment (2016)
  • Author(s): Kurosaki, T.
  • Organizer: Antibody and Fc Receptor Biology: Bench to Bedside A Special Symposium to Honor Jeffrey V. Ravetch on his 65th Birthday
  • Place of Presentation: New York, USA
  • Year and Date: 2016-05-09
  • Int'l Joint Research / Invited
• [Presentation] B細胞を介する自己免疫抑制 (2016)
  • Author(s): 黒崎知博
  • Organizer: 第60回日本リウマチ学会総会・学術集会
  • Place of Presentation: パシフィコ横浜、横浜
  • Year and Date: 2016-04-21 – 2016-04-23
  • Invited
• [Remarks] Laboratory of Lymphocyte Differentiation
  • URL: http://lymph.ifrec.osaka-u.ac.jp/index_j.html