Analysis of Egr2-expressing regulatory T cells in mice and human

• Project/Area Number: 24390252
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Partial Multi-year Fund
• Section: 一般
• Research Field: 膠原病・アレルギー・感染症内科学
• Research Institution: The University of Tokyo
• Principal Investigator: FUJIO KEISHI 東京大学, 医学部附属病院, 講師 (70401114)
• Project Period (FY): 2012-04-01 – 2015-03-31
• Project Status: Completed (Fiscal Year 2014)
• Budget Amount: ¥17,550,000 (Direct Cost: ¥13,500,000、Indirect Cost: ¥4,050,000); Fiscal Year 2014: ¥5,200,000 (Direct Cost: ¥4,000,000、Indirect Cost: ¥1,200,000); Fiscal Year 2013: ¥5,720,000 (Direct Cost: ¥4,400,000、Indirect Cost: ¥1,320,000); Fiscal Year 2012: ¥6,630,000 (Direct Cost: ¥5,100,000、Indirect Cost: ¥1,530,000)
• Keywords: 自己免疫疾患 / 制御性T細胞 / TGF-beta / 免疫抑制療法 / サイトカイン / 自己反応性B細胞 / JAKキナーゼ / STAT / 抗体産生

Outline of Final Research Achievements

We previously described that CD4+CD25-LAG3+regulatory T cells(LAG3+ Treg) are regulated by Egr2, a zinc-finger transcription factor required for the
induction of T-cell anergy.We herein demonstrate that LAG3+Treg produce high amounts ofTGF-beta3 in an Egr2- and Fas-dependent manner. LAG3+Treg require TGF-beta3 to suppress B-cell responses in a murine model of lupus. Moreover, TGF-beta3- and LAG3+Treg-mediated suppression requires PD-1 expression on B cells. We also show that TGF-beta3-expressing human LAG3+Treg suppress antibody production and that SLE patients exhibit decreased frequencies of LAG3+Treg. These results clarify the mechanism of B-cell regulation and suggest therapeutic strategies.

Research Products

• [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] 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] 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] 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: 4 Pages: 1060-1060
  • DOI: 10.1002/art.38330
  • Peer Reviewed
• [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] 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 Issue: suppl 2 Pages: 1-8
  • DOI: 10.1136/annrheumdis-2012-202341
  • Peer Reviewed
• [Journal Article] Kidney-infiltrating T cell clones promote nephritis in lupus-prone mice (2012)
  • Author(s): Okamoto A, Fujio K, Tsuno NH, Takahashi K, Yamamoto K
  • Journal Title: Kidney Int. Volume: 8 Issue: 9 Pages: 969-79
  • DOI: 10.1038/ki.2012.242
  • Peer Reviewed
• [Journal Article] Roles of LAG3 and EGR2 in regulatory T cells. (2012)
  • Author(s): Tomohisa Okamura
  • Journal Title: Ann Rheum Dis Volume: 71 Issue: Suppl 2 Pages: 96-100
  • DOI: 10.1136/annrheumdis-2011-200588
  • Peer Reviewed
• [Presentation] TGF-beta3-expressing CD4+CD25-LAG3+ regulatory T cells control humoral immune responses. (2014)
  • Author(s): Keishi Fujio.
  • Organizer: 第43回日本免疫学会学術総会 国際シンポジウム
  • Place of Presentation: 京都国際会議場
  • Year and Date: 2014-12-10 – 2014-12-12
• [Presentation] TGF-beta3産生によるCD4陽性CD25陰性LAG3陽性制御性T細胞のB細胞機能抑制 (2014)
  • Author(s): 藤尾圭志
  • Organizer: 第79回日本インターフェロンサイトカイン学会
  • Place of Presentation: 北海道大学
  • Year and Date: 2014-06-19 – 2014-06-20
  • Invited
• [Presentation] CD4+CD25-LAG3+ regulatory T cells and systemic autoimmunity. (2014)
  • Author(s): Keishi Fujio, Tomohisa Okamura, Kaoru Morita, Mariko Inoue, Yukiko Iwasaki, Shuji Sumitomo, Shinichiro Nakachi, Kazuhiko, Yamamoto.
  • Organizer: 第58回日本リウマチ学会（東京）国際リウマチシンポジウム
  • Place of Presentation: 新高輪プリンスホテル
  • Year and Date: 2014-04-24 – 2014-04-26
• [Presentation] 全身性エリテマトーデスと免疫制御細胞 (2013)
  • Author(s): 藤尾圭志
  • Organizer: 第57回日本リウマチ学会総会 シンポジウム
  • Place of Presentation: 国立京都国際会館
• [Presentation] The B cell control by EGR-2 expressing CD4+CD25-LAG3+ regulatory T cells (2013)
  • Author(s): Keishi Fujio
  • Organizer: Autoimmunity Congress Asia
  • Place of Presentation: Hong Kong Academy of Science
  • Invited
• [Presentation] The role of CD4+CD25-LAG3+ regulatory T cells in autoimmune diseses (2013)
  • Author(s): Keishi Fujio
  • Organizer: Annual Meeting of Japanease Society for Immunology, 2013
  • Place of Presentation: Makuhari Messe
• [Presentation] CD4+CD25-LAG3+ regulatory T cells and autoimmunity (2012)
  • Author(s): KEISHI FUJIO (invited)
  • Organizer: 8^<th> International Congress on Autoimmunity Satellite Symposium: Recent Progress in Autoimmune Research in Japan
  • Place of Presentation: Granada, Spain
  • Year and Date: 2012-05-10
• [Presentation] 制御性T細胞と自己免疫 (2012)
  • Author(s): 藤尾圭志
  • Organizer: 第56回日本リウマチ学会総会
  • Place of Presentation: 高輪、東京
  • Year and Date: 2012-04-27
• [Remarks] 東京大学医学部アレルギー・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第18研究室
  • URL: http://plaza.umin.ac.jp/areriu18/
• [Remarks]
  • 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