Cytokine synergy-mediated control of humoral immune tolerance

• Project/Area Number: 16K09918
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Collagenous pathology/Allergology
• Research Institution: The University of Tokyo
• Principal Investigator: Okamura Tomohisa 東京大学, 医学部附属病院, 特任助教 (10528996)
• Research Collaborator: Sumitomo Shuji
• Project Period (FY): 2016-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000); Fiscal Year 2018: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2017: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2016: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: 制御性T細胞 / 自己抗体 / 全身性エリテマトーデス / TGF-β / IL-10 / LAG3 / B細胞 / TGF-beta / 自己免疫疾患 / サイトカイン / 液性免疫

Outline of Final Research Achievements

CD4+CD25-LAG3+ regulatory T cells produce a large amount of IL-10 and TGF-β3, and effectively suppress humoral immune responses. However, the mechanisms behind the inhibitory cytokine synergy mediated by IL-10 and TGF-β3 are unclear. In this study, we revealed that IL-10 and TGF-β3 synergistically regulate humoral immunity via modulating mTORC1 signaling in B cells. These findings indicate that the cytokine combination therapy with IL-10 and TGF-β3 might be an effective approach for the treatment of autoimmune diseases.

Academic Significance and Societal Importance of the Research Achievements

免疫抑制機構の中心的サイトカインはTGF-β とIL-10 が広く知られているが、共に免疫に対して促進性にも抑制性にも働くという側面があり、臨床応用への大きなハードルとなっている。当研究室で同定した LAG3 Tregは両サイトカインを大量に産生し、かつ抗体産生の強力な抑制能を有する。本研究では、両サイトカインが単独ではなく協調することで抑制能を発揮する「抑制性サイトカイン協調(inhibitory Cytokine Synergy: ICS)作用」の詳細なメカニズムを初めて明らかにした。本知見は、自己抗体産生機序を介した自己免疫疾患の新規治療法に繋がる可能性を内包している。

Research Products

• [Journal Article] Reevaluation of Pluripotent Cytokine TGF-β3 in Immunity (2018)
  • Author(s): Toshihiko Komai, Tomohisa Okamura, Mariko Inoue, Kazuhiko Yamamoto, Keishi Fujio
  • Journal Title: International Journal of Molecular Sciences Volume: 19 Issue: 8 Pages: 1-15
  • DOI: 10.3390/ijms19082261
  • Peer Reviewed / Open Access
• [Journal Article] Transforming Growth Factor-β and Interleukin-10 Synergistically Regulate Humoral Immunity via Modulating Metabolic Signals. (2018)
  • Author(s): Komai T, Inoue M, Okamura T, Morita K, Iwasaki Y, Sumitomo S, Shoda H, Yamamoto K, Fujio K.
  • Journal Title: Front Immunol Volume: 9 Pages: 1364-1364
  • DOI: 10.3389/fimmu.2018.01364
  • Peer Reviewed / Open Access
• [Journal Article] Egr2-independent, Klf1-mediated induction of PD-L1 in CD4+ T cells. (2018)
  • Author(s): Teruya S, Okamura T, Komai T, Inoue M, Iwasaki Y, Sumitomo S, Shoda H, Yamamoto K, Fujio K.
  • Journal Title: Scientific Reports Volume: 8 Issue: 1 Pages: 7021-7021
  • DOI: 10.1038/s41598-018-25302-1
  • Peer Reviewed / Open Access
• [Journal Article] Early Growth Response Gene 2-Expressing CD4+LAG3+ Regulatory T Cells: The Therapeutic Potential for Treating Autoimmune Diseases (2018)
  • Author(s): Okamura Tomohisa、Yamamoto Kazuhiko、Fujio Keishi
  • Journal Title: Frontiers in Immunology Volume: 9 Pages: 1-9
  • DOI: 10.3389/fimmu.2018.00340
  • Peer Reviewed / Open Access
• [Journal Article] Overview of LAG-3-Expressing, IL-10-Producing Regulatory T Cells (2017)
  • Author(s): Fujio Keishi、Yamamoto Kazuhiko、Okamura Tomohisa
  • Journal Title: Curr Top Microbiol Immunol Volume: 410 Pages: 29-45
  • DOI: 10.1007/82_2017_59
  • ISBN: 9783319689289, 9783319689296
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] The metabolic regulation in immune cells and pathogenesis of systemic lupus erythematosus ∼toward new therapeutic applications∼ (2017)
  • Author(s): 竹島 雄介、岩崎 由希子、岡村 僚久、藤尾 圭志、山本 一彦
  • Journal Title: Japanese Journal of Clinical Immunology Volume: 40 Issue: 1 Pages: 12-20
  • DOI: 10.2177/jsci.40.12
  • NAID: 130005665586
  • ISSN: 0911-4300, 1349-7413
• [Journal Article] Interleukin-10-producing LAG3+ regulatory T cells are associated with disease activity and abatacept treatment in rheumatoid arthritis (2017)
  • Author(s): Nakachi Shinichiro、Sumitomo Shuji、Tsuchida Yumi、Tsuchiya Haruka、Kono Masanori、Kato Rika、Sakurai Keiichi、Hanata Norio、Nagafuchi Yasuo、Tateishi Shoko、Kanda Hiroko、Okamura Tomohisa、Yamamoto Kazuhiko、Fujio Keishi
  • Journal Title: Arthritis Research & Therapy Volume: 19 Issue: 1 Pages: 1-11
  • DOI: 10.1186/s13075-017-1309-x
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Egr2 and Egr3 in regulatory T cells cooperatively control systemic autoimmunity through Ltbp3-mediated TGF-β3 production. (2016)
  • Author(s): Morita K, Okamura T, Inoue M, Komai T, Teruya S, Iwasaki Y, Sumitomo S, Shoda H, Yamamoto K, Fujio K.
  • Journal Title: Proc. Natl. Acad. Sci. U S A. Volume: 113 Issue: 50 Pages: 8131-8140
  • DOI: 10.1073/pnas.1611286114
  • Peer Reviewed / Open Access
• [Journal Article] Emerging roles of Egr2 and Egr3 in the control of systemic autoimmunity. (2016)
  • Author(s): Morita K, Okamura T, Sumitomo S, Iwasaki Y, Fujio K, Yamamoto K.
  • Journal Title: Rheumatology (Oxford) Volume: 55(suppl 2) Issue: suppl 2 Pages: 76-81
  • DOI: 10.1093/rheumatology/kew342
  • Peer Reviewed
• [Journal Article] The effects of TGF-βs on immune responses (2016)
  • Author(s): Fujio K, Komai T, Inoue M, Morita K, Okamura T, Yamamoto K.
  • Journal Title: Japanese Journal of Clinical Immunology Volume: 39 Issue: 1 Pages: 51-58
  • DOI: 10.2177/jsci.39.51
  • NAID: 130005151098
  • ISSN: 0911-4300, 1349-7413
  • Peer Reviewed
• [Journal Article] The effects of TGF-βs on immune responses. (2016)
  • Author(s): Komai T, Okamura T, Yamamoto K, Fujio K.
  • Journal Title: Nihon Rinsho Meneki Gakkai Kaishi. Volume: 39 Pages: 51-58
  • NAID: 130005151098
• [Presentation] Role of CD4+CD25-LAG3+ regulatory T cells in the maintenance of humoral immune tolerance (2018)
  • Author(s): 岡村僚久
  • Organizer: 第47回日本臨床免疫学会総会
  • Invited
• [Presentation] B cell regulation through modulation of autophagy by inhibitory cytokines (2018)
  • Author(s): Mariko Inoue,Tomohisa Okamura,Toshihiko Komai,Morita Kaoru,Yukiko Iwasaki,Shuji Sumitomo,Hirofumi Shoda,Kazuhiko Yamamoto, Keishi Fujio
  • Organizer: 第47回日本免疫学会学術集会
• [Presentation] Cytokine-mediated Immune tolerance via mitochondrial reprogramming (2018)
  • Author(s): Toshihiko Komai,Tomohisa Okamura,Mariko Inoue1, Morita Kaoru,Yukiko Iwasaki,Shuji Sumitomo, Hirofumi Shoda,Kazuhiko Yamamoto, Keishi Fujio
  • Organizer: 第47回日本免疫学会学術集会
• [Presentation] Role of Egr2/Egr3 in regulatory T cell-mediated humoral immune tolerance (2017)
  • Author(s): Tomohisa Okamura
  • Organizer: 4th Symposium on Max Planck-The University of Tokyo Center for Integrative
  • Int'l Joint Research
• [Presentation] CD4陽性T細胞における転写因子Klf1を介したPD-L1発現誘導機構 (2017)
  • Author(s): 照屋周造、岡村僚久、竹島雄介、駒井俊彦、井上真璃子、岩崎由希子、山本一彦、藤尾圭志
  • Organizer: 第45回日本臨床免疫学会総会
• [Presentation] Immunological significance of dual secretion of TGF-beta3 and IL-10 from regulatory T cells (2016)
  • Author(s): Toshihiko Komai, Tomohisa Okamura, Mariko Inoue, Yukiko Iwasaki, Kaoru Morita, Kazuhiko Yamamoto, Keishi Fujio
  • Organizer: 第45回 日本免疫学会総会・学術集会
  • Place of Presentation: 沖縄コンベンションセンター（沖縄県）
  • Year and Date: 2016-12-05
• [Presentation] TGF-β3およびIL-10による協調性液性免疫制御機構の解明 (2016)
  • Author(s): 井上眞璃子、岡村僚久、駒井俊彦、森田薫、照屋周造、岩崎由希子、住友秀次、山本一彦、藤尾圭志
  • 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（神奈川県）
  • Year and Date: 2016-04-21
• [Book] 週刊『医学のあゆみ』「制御性T細胞の現在」268巻13号「LAG3陽性制御性T細胞の分化と機能」 (2019)
  • Author(s): 岡村僚久
  • Total Pages: 6
  • Publisher: 医歯薬出版株式会社
• [Book] 「Precision Medicine」2019年1月号 「自己免疫疾患の個別化医療 Personalized medicine of autoimmune disease」 (2018)
  • Author(s): 岡村僚久
  • Total Pages: 5
  • Publisher: 北隆館
• [Book] 週刊『医学のあゆみ』「Class Ib拘束性T細胞研究の新展開・Qa1拘束性T細胞の分化と機能における新展開」265巻4号 「Qa-1拘束性CD8陽性制御性T細胞の分化と機能」 (2018)
  • Author(s): 岡村僚久
  • Total Pages: 4
  • Publisher: 医歯薬出版株式会社
• [Book] 「リウマチ科」vol.58 no.5 (11月号) 特集「免疫学の基本的知識およびリウマチ性疾患との関連について理解する」 (2017)
  • Author(s): 岡村僚久
  • Total Pages: 6
  • Publisher: 科学評論社
• [Book] 「分子リウマチ治療」vol.9 no.3 (2016年8月号) 連載「疾患からみた細胞表面機能分子」 (2016)
  • Author(s): 岡村僚久
  • Total Pages: 6
  • Publisher: 先端医学社
• [Remarks] 東京大学医学部附属病院 アレルギーリウマチ内科
  • URL: http://ryumachi.umin.jp/about/research.html
• [Remarks] 東京大学医学部附属病院 アレルギーリウマチ内科 第18研究室
  • URL: http://plaza.umin.ac.jp/areriu18/