Regulation of autoantibody production by regulatory T cells expressing anergy-associated genes

• Project/Area Number: 25461493
• 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, 助教 (10528996)
• Project Period (FY): 2013-04-01 – 2016-03-31
• Project Status: Completed (Fiscal Year 2015)
• Budget Amount: ¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000); Fiscal Year 2015: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2014: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2013: ¥2,340,000 (Direct Cost: ¥1,800,000、Indirect Cost: ¥540,000)
• Keywords: 制御性T細胞 / 自己抗体 / 全身性エリテマトーデス / LAG3 / Egr2 / TGF-β / TGF-β3

Outline of Final Research Achievements

Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by autoantibody production and associated with a wide range of clinical manifestations. Early growth response gene-2 (EGR2), a zinc-finger transcription factor, is known to affect susceptibility to SLE in human. We previously reported CD4+CD25-Foxp3-LAG3+ regulatory T cells (LAG3 Tregs) that characteristically express Egr2. In this study, we revealed that LAG3 Tregs, but not CD4+CD25+ Tregs, produce enormous amounts of TGF-β3 in an Egr2-dependent manner. TGF-β3 effectively suppressed autoantibody production from B cells through suppression of Syk, STAT6, and NF-κB pathways. Intriguingly, Egr3 was able to compensate the function of Egr2. These findings elucidated the mechanisms of T cell anergy-associated gene Egr2-mediated regulation of humoral immunity.

Research Products

• [Journal Article] Therapeutic potential of regulatory cytokines that target B cells. (2016)
  • Author(s): Fujio Keishi, Okamura Tomohisa, Sumitomo Shuji, Yamamoto Kazuhiko
  • Journal Title: Internal Immunology Volume: 28 Issue: 4 Pages: 189-195
  • DOI: 10.1093/intimm/dxv069
  • Peer Reviewed / Open Access
• [Journal Article] 1.Immune responses to Mycobacterium heat shock protein 70 accompany self-reactivity to human BiP in rheumatoid arthritis (2016)
  • Author(s): Shoda H, Hanata N, Sumitomo S, Okamura T, Fujio K, Yamamoto K
  • Journal Title: Scientific Reports Volume: 6 Issue: 1 Pages: 22486-22486
  • DOI: 10.1038/srep22486
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] A new T-cell activation mode for suboptimal doses of antigen under the full activation of T cells with different specificity. (2015)
  • Author(s): Shibuya M, Fujio K, Shoda H, Okamura T, Okamoto A, Sumitomo S, Yamamoto K.
  • Journal Title: Europian Journal of Immunology Volume: in press Issue: 6 Pages: 1643-53
  • DOI: 10.1002/eji.201444965
  • Peer Reviewed
• [Journal Article] Role of TGF-β3 in the regulation of immune responses. (2015)
  • Author(s): Okamura T, Morita K, Iwasaki Y, Inoue M, Komai T, Fujio K, Yamamoto K.
  • Journal Title: Clin Exp Rheumatol. Volume: 33 Pages: 63-69
  • Peer Reviewed / Open Access
• [Journal Article] TGF-β3-expressing CD4+CD25(-)LAG3+ regulatory T cells control humoral immune responses (2015)
  • Author(s): Okamura T, Sumitomo S, Morita K, Iwasaki Y, Inoue M, Nakachi S, Komai T, Shoda H, Miyazaki J, Fujio K, Yamamoto K.
  • Journal Title: Nature Communications Volume: 6 Issue: 1 Pages: 1-14
  • DOI: 10.1038/ncomms7329
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Interleukin-27 in T cell immunity. (2015)
  • Author(s): Iwasaki Y, Fujio K, Okamura T, Yamamoto K
  • Journal Title: Int J Mol Sci Volume: 16 Issue: 2 Pages: 2851-63
  • DOI: 10.3390/ijms16022851
  • Peer Reviewed / Open Access
• [Journal Article] Regulatory T cells in systemic lupus erythematosus (2015)
  • Author(s): Okamura T, Morita K, Fujio K, Yamamoto K
  • Journal Title: Japanese Journal of Clinical Immunology Volume: 38 Issue: 1 Pages: 69-77
  • DOI: 10.2177/jsci.38.69
  • NAID: 130004875954
  • ISSN: 0911-4300, 1349-7413
  • Open Access
• [Journal Article] Autoantigen BiP-derived HLA-DR4 epitopes differentially recognized by effector and regulatory T cells in rheumatoid arthritis. (2015)
  • Author(s): Shoda H, Fujio K, Sakurai K, Ishigaki K, Nagafuchi Y, Shibuya M, Sumitomo S, Okamura T, Yamamoto K
  • Journal Title: Arthritis and Rheumatology Volume: in press Issue: 5 Pages: 1171-81
  • DOI: 10.1002/art.39054
  • Peer Reviewed
• [Journal Article] The functions of CD4+CD25-LAG3+ regulatory T cells and Egr2 in the regulation of autoimmunity. (2014)
  • Author(s): Fujio K, Okamura T, Sumitomo S, Yamamoto K.
  • Journal Title: Nihon Rinsho Meneki Gakkai Kaishi. Volume: 37 Pages: 69-73
  • NAID: 130004875917
  • Open Access
• [Journal Article] Transcription factor early growth response 3 is associated with the TGF-β1 expression and the regulatory activity of CD4-positive T cells in vivo. (2013)
  • Author(s): Sumitomo S, Fujio K, Okamura T, Morita K, Ishigaki K, Suzukawa K, Kanaya K, Kondo K, Yamasoba T, Furukawa A, Kitahara N, Shoda H, Shibuya M, Okamoto A, Yamamoto K.
  • Journal Title: J Immunol Volume: 191 Issue: 5 Pages: 2351-9
  • DOI: 10.4049/jimmunol.1202106
  • Peer Reviewed
• [Journal Article] Toward therapeutic application of IL-10-producing regulatory T cells (2013)
  • Author(s): Iwasaki Y, Fujio K, Okamura T, Yanai A, Yamamoto K.
  • Journal Title: Journal Clinical Immunology Volume: 36 Pages: 40-46
• [Journal Article] Egr2 and Egr3 are the unique regulators for systemic autoimmunity. (2013)
  • Author(s): Sumitomo S, Fujio K, Okamura T, Yamamoto K.
  • Journal Title: JAKSTAT Volume: 2 Issue: 2 Pages: e23952-e23952
  • DOI: 10.4161/jkst.23952
  • Peer Reviewed
• [Journal Article] Egr-2 transcription factor is required for Blimp-1 mediated IL-10 production in IL-27 stimulated CD4(+) T cells (2013)
  • Author(s): Iwasaki, Y.
  • Journal Title: Eur J Immunol Volume: undefined Issue: 4 Pages: 1063-73
  • DOI: 10.1002/eji.201242942
  • Peer Reviewed
• [Journal Article] Regulatory cell subsets in the control of autoantibody production related to systemic autoimmunity. (2013)
  • Author(s): Fujio K, Okamura T, Sumitomo S, Yamamoto K.
  • Journal Title: Ann Rheum Dis Volume: 72 Pages: 1-8
  • DOI: 10.1136/annrheumdis-2012-202341
  • Peer Reviewed
• [Journal Article] (2012)
  • Author(s): Izawa S, Okamura T, Matsuzawa K, Ohkura T, Ohkura H, Ishiguro K, Noh JY, Kamijo K, Yoshida A, Shigemasa C, Kato M, Yamamoto K, Taniguchi SI
  • Journal Title: Clin Endocrinol (Oxf) Volume: 79 Issue: 1 Pages: 35-42
  • DOI: 10.1111/cen.12121
  • Peer Reviewed
• [Presentation] Inhibitory Synergistic Effect of TGF-beta and IL-10 on Humoral Immunity (2015)
  • Author(s): Tomohisa Okamura, Kaoru Morita, Mariko Inoue, Toshihiko Komai, Yukiko Iwasaki, Shuji Sumitomo, Shinichiro Nakachi, Hirofumi Shoda, Keishi Fujio, and Kazuhiko Yamamoto
  • Organizer: The Second Symposium on Max Planck-The University of Tokyo Center for Integrative Inflammology
  • Place of Presentation: 東京大学 山上会館（東京都・文京区）
  • Year and Date: 2015-10-26
  • Int'l Joint Research
• [Presentation] B 細胞を制御するT 細胞 (2015)
  • Author(s): 岡村僚久
  • Organizer: 第43回日本臨床免疫学会総会
  • Place of Presentation: 神戸国際会議場（兵庫県・中央区）
  • Year and Date: 2015-10-22
  • Invited
• [Presentation] Regulation of humoral immune responses by TGF-β-producing CD4+CD25-LAG3+ regulatory T cells (2015)
  • Author(s): Tomohisa Okamura, Kaoru Morita, Yukiko Iwasaki, Mriko Inoue, Toshihiko Komai, Shuji Sumitomo, Shinichiro Nakachi, Hirofumi Shoda, Keishi Fujio, Kazuhiko Yamamoto
  • Organizer: 第59回日本リウマチ学会学術集会
  • Place of Presentation: 名古屋国際会議場（名古屋）
  • Year and Date: 2015-04-23 – 2015-04-25
• [Presentation] Regulation of humoral immune responses by TGF-β-producing CD4+CD25-LAG3+ regulatory T cells immunity (2015)
  • Author(s): OKAMURA Tomohisa, MORITA Kaoru, INOUE Mariko, IWASAKI Yukiko, SUMITOMO Shuji, KOMAI Toshihiko, SHODA Hirofumi, FUJIO Keishi, & YAMAMOTO Kazuhiko
  • Organizer: 第59回日本リウマチ学会総会・学術集会
  • Place of Presentation: 名古屋国際会議場（愛知県・名古屋市）
  • Year and Date: 2015-04-21
• [Presentation] CD4陽性CD25陰性LAG3陽性 制御性T細胞による液性免疫制御機構 (2015)
  • Author(s): 岡村僚久
  • Organizer: 第1回 T Cell Seminar
  • Place of Presentation: 帝国ホテル（東京都）
  • Year and Date: 2015-02-10
  • Invited
• [Presentation] TGF-β3-Producing CD4+CD25-LAG3+ Regulatory T Cells Control B Cell Responses (2014)
  • Author(s): Tomohisa Okamura, Kaoru Morita, Mariko Inoue, Toshihiko Komai, Yukiko Iwasaki, Shuji Sumitomo, Shinichiro Nakachi, Hirofumi Shoda, Keishi Fujio, and Kazuhiko Yamamoto
  • Organizer: The First Symposium on Max Planck-The University of Tokyo Center for Integrative Inflammology
  • Place of Presentation: Harnack House, Berlin（ドイツ）
  • Year and Date: 2014-12-16 – 2014-12-18
• [Presentation] TGF-β3-producing CD4+CD25-LAG3+ regulatory T cells control humoral immunity (2014)
  • Author(s): OKAMURA Tomohisa, MORITA Kaoru, INOUE Mariko, IWASAKI Yukiko, SUMITOMO Shuji, KOMAI Toshihiko, SHODA Hirofumi, FUJIO Keishi, & YAMAMOTO Kazuhiko
  • Organizer: 第43回日本免疫学会学術集会
  • Place of Presentation: 国立京都国際会館（京都）
  • Year and Date: 2014-12-10 – 2014-12-12
• [Presentation] CD4陽性CD25陰性LAG3陽性制御性T細胞による自己抗体産生制御機構 (2014)
  • Author(s): 岡村僚久、藤尾圭志、森田薫、井上眞璃子、駒井俊彦、岩崎由希子、住友秀次、渋谷美穂子、庄田宏文、山本一彦
  • Organizer: 第42回日本臨床免疫学会総会
  • Place of Presentation: 京王プラザホテル（東京都）
  • Year and Date: 2014-09-25 – 2014-09-27
• [Presentation] CD4+CD25-LAG3+ regulatory T cells controls excessive B cell responses (2014)
  • Author(s): Tomohisa Okamura, Keishi Fujio, Kaoru Morita, Yukiko Iwasaki, Mariko Inoue, Toshihiko Komai, Shuji Sumitomo, Mihoko Shibuya, Hirofumi Shoda, and Kazuhiko Yamamoto
  • Organizer: 第58回日本リウマチ学会学術集会
  • Place of Presentation: グランドプリンスホテル新高輪 (東京都)
  • Year and Date: 2014-04-24 – 2014-04-26
• [Presentation] CD4＋CD25－LAG3＋ 制御性T細胞による免疫制御機構 (2014)
  • Author(s): 岡村僚久
  • Organizer: 第2回 明石町リウマチ連携セミナー
  • Place of Presentation: 聖路加国際病院 トイスラー記念ホール 東京都
  • Invited
• [Presentation] CD4+CD25-LAG3+ regulatory T cells controls excessive B cell responses (2013)
  • Author(s): 岡村僚久、藤尾圭志、森田薫、井上眞璃子、駒井俊彦、住友秀次、渋谷美穂子、庄田宏文、岩崎由希子、山本一彦
  • Organizer: 第58回 日本リウマチ学会総会・学術集会
  • Place of Presentation: グランドニュープリンスホテル高輪 東京都
• [Presentation] CD4+CD25-LAG3+ regulatory T cell controls excessive B cell antibody production and systemic autoimmunity (2013)
  • Author(s): 岡村僚久、藤尾圭志、渋谷美穂子、住友秀次、庄田宏文、岩崎由希子、森田薫、井上眞璃子、山本一彦
  • Organizer: 第42回 日本免疫学会学術集会
  • Place of Presentation: 幕張メッセ 千葉県
• [Book] 『分子リウマチ治療』vol.9 no.3 『疾患からみた細胞表面機能分子』 SLEにおけるLAG3+細胞 (2016)
  • Author(s): 岡村僚久
  • Publisher: 先端医学社
• [Book] 「Pharma Medica」自己免疫疾患の最近の話題と展望 特集号「自己免疫疾患のエフェクターT細胞と抑制性T細胞」 (2013)
  • Author(s): 岡村僚久
  • Total Pages: 11
  • Publisher: メディカルレビュー社
• [Book] 制御性Ｔ細胞 - その基礎と臨床展開 (2013)
  • Author(s): ＣＤ４＋ＣＤ２５－ＬＡＧ３＋制御性T細胞による免疫制御
  • Total Pages: 5
  • Publisher: 医学のあゆみ
• [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/project.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/
• [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://plaza.umin.ac.jp/areriu18/
• [Patent(Industrial Property Rights)] Ｂ細胞活性化の抑制剤及び自己免疫疾患の治療剤 (2014)
  • Inventor(s): 藤尾圭志、岡村僚久、山本一彦、森田薫、駒井俊彦
  • Industrial Property Rights Holder: 藤尾圭志、岡村僚久、山本一彦、森田薫、駒井俊彦
  • Industrial Property Rights Type: 特許
  • Filing Date: 2014-11-28