Regulation of T cell response and homeostasis by the TGFbeta/beta-catenin signals

• Project/Area Number: 23390075
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: General medical chemistry
• Research Institution: Ehime University (2012-2013); Kazusa DNA Research Institute (2011)
• Principal Investigator: YAMASHITA Masakatsu 愛媛大学, 医学(系)研究科(研究院), 教授 (00311605)
• Project Period (FY): 2011-04-01 – 2014-03-31
• Project Status: Completed (Fiscal Year 2013)
• Budget Amount: ¥18,850,000 (Direct Cost: ¥14,500,000、Indirect Cost: ¥4,350,000); Fiscal Year 2013: ¥3,770,000 (Direct Cost: ¥2,900,000、Indirect Cost: ¥870,000); Fiscal Year 2012: ¥6,760,000 (Direct Cost: ¥5,200,000、Indirect Cost: ¥1,560,000); Fiscal Year 2011: ¥8,320,000 (Direct Cost: ¥6,400,000、Indirect Cost: ¥1,920,000)
• Keywords: 分子病態学 / 免疫 / アレルギー / 老化 / Menin / Tcf7 / Th2 / 炎症 / β-catenin / OX40 / αβT細胞 / γδT細胞 / 好酸球

Research Abstract

Sox4 is a transcription factor that regulates various developmental processes. We found that Sox4 was induced by TGFbeta and negatively regulated the transcription factor Gata3, the master regulator of Th2 cell development and allergic inflammation, by two distinct mechanisms. First, Sox4 bound to GATA3, preventing its binding to GATA3 consensus DNA sequences. Second, Sox4 bound to the promoter region of the gene encoding IL-5, a Th2 cytokine, and preventing binding of GATA3 to this promoter. Th2 driven airway inflammation was modulated by alterations in Sox4 expression. Thus, Sox4 acts as a downstream target of TGFbeta to inhibit GATA3 function and Th2-dependent allergic inflammation.

Research Products

• [Journal Article] Menin-Bach2 axis is critical for regulating CD4 T-cell senescence and cytokine homeostasis (2014)
  • Author(s): Kuwahara M, Suzuki J ., Tofukuji S, Yamada T, Kanoh M, Matsumoto A, Maruyama S, Kometani K, Kurosaki T, Ohara O, Nakayama T and Yamashita, M
  • Journal Title: Nat. Commun Volume: 5 Pages: 3555-3555
  • Peer Reviewed
• [Journal Article] The Menin-Bach2 axis is critical for regulating CD4 T cell senescence and cytokine homeostasis (2014)
  • Author(s): Kuwahara, M., Suzuki, J., Tofukuji, S., Yamada, T., Kanoh, M., Matsumoto, A., Maruyama, S., Kometani, K., Kurosaki, T., Ohara, O., Nakayama, T., Yamashita, M
  • Journal Title: Nature Comm Volume: 5 Issue: 1 Pages: 3555-3555
  • DOI: 10.1038/ncomms4555
  • Peer Reviewed / Open Access
• [Journal Article] The transcription factor Sox4 is a downstream target of signaling by the cytokine TGF-β and suppresses T_H2 differentiation (2012)
  • Author(s): Kuwahara M, Yamashita M, Shinoda K, Tofukuji S, Onodera A, Shinnakasu R, Motohashi S, Hosokawa H, Tumes D, Iwamura C, Lefebvre V and Nakayama T.
  • Journal Title: Nat. Immunol Volume: 13 Pages: 778-786
  • Peer Reviewed
• [Journal Article] Identification of a new pathway for Th1 cell development induced by cooperative stimulation with IL-4 and TGFβ (2012)
  • Author(s): Tofukuji S, Kuwahara M, Suzuki J, Ohara O, Nakayama T, and Yamashita M
  • Journal Title: J. Immunol Volume: 188 Pages: 4846-4857
  • Peer Reviewed
• [Journal Article] The transcription factor Sox4 is a downstream target of signaling by the cytokine TGF-・ and suppresses TH2 differentiation (2012)
  • Author(s): Kuwahara, M., Yamashita, M., Shinoda, K., Tofukuji, S., Onodera, A., Shinnakasu, R., Motohashi, S., Hosokawa, H., Tumes, D., Iwamura, C., Lefebvre, V., and Nakayama, T.
  • Journal Title: Nat. Immunol Volume: 13(8) Issue: 8 Pages: 778-786
  • DOI: 10.1038/ni.2362
  • Peer Reviewed
• [Presentation] Menin inhibits transcription programs that promote CD4 T cell senescence and Th1/Th2 differentiation (2013)
  • Author(s): Kuwahara M, Yamada T, Nakayama T, Yamashita M.
  • Organizer: 第42回日本免疫学会総会・学術集会
  • Place of Presentation: 幕張メッセ
• [Presentation] Crutial role of Menin in the regulation of CD4 T cell terminal differentiation and senescence (2013)
  • Author(s): Kuwahara M, Nakayama T, Yamashita M.
  • Organizer: The 6th International Workshop of Kyoto T Cell Conference
  • Place of Presentation: 京都大学
• [Presentation] TGFβはIL-4をTh1細胞分化誘導因子へと変換する (2012)
  • Author(s): 東福寺聡一,桑原誠,鈴木淳平,中山俊憲,小原収,山下政克
  • Organizer: 第22回Kyoto T Cell Conference
  • Place of Presentation: 京都
• [Presentation] HMG box 型転写因子Sox4はTGFβ刺激で誘導され, Th2細胞分化を抑制する (2012)
  • Author(s): 桑原誠,鈴木淳平,東福寺聡一,中山俊憲,小原収,山下政克
  • Organizer: 第22回Kyoto T Cell Conference
  • Place of Presentation: 京都
• [Presentation] Menin-Bach2 axis controls senescence-associated secretory phenotype (SASP) in CD4 T cells (2012)
  • Author(s): 桑原誠
  • Organizer: 第41回日本免疫学会総会・学術総会
  • Place of Presentation: 神戸
• [Presentation] TGFβはIL-4をThl細胞分化誘導因子へと変換する (2011)
  • Author(s): 東福寺聡一
  • Organizer: 第40回日本免疫学会学術集会
  • Place of Presentation: 千葉
  • Year and Date: 2011-11-27
• [Presentation] TGFβはIL-4をThl細胞分化誘導因子へと変換する (2011)
  • Author(s): 東福寺聡一
  • Organizer: 第21回Kyoto T Cell Conference
  • Place of Presentation: 京都
  • Year and Date: 2011-06-11
• [Presentation] TGFβ converts IL-4 into a Th1 cell inducer (2011)
  • Author(s): TOFUKUJI Soichi, KUWAHARA Makoto, SUZUKI Junpei, OHARA Osamu, NAKAYAMA Toshinori, YAMASHITA Masakatsu
  • Organizer: 第40回日本免疫学会総会・学術集会
  • Place of Presentation: 幕張市
• [Presentation] Sox4 acts as a downstream target of TGFβ and suppresses Th2 type immune responses (2011)
  • Author(s): KUWAHARA Makoto, IWAMURA Chiaki, SHINODA Kenta, TOFUKUJI Soichi, SUZUKI Junpei, NAKAYAMA Toshinori, YAMASHITA Masakatsu
  • Organizer: 第40回日本免疫学会総会・学術集会
  • Place of Presentation: 幕張市
• [Presentation] Th2 細胞分化・機能の調節を介した気道炎症制御 (2011)
  • Author(s): 山下政克,東福寺聡一,鈴木淳平,桑原誠
  • Organizer: 第48回日本小児アレルギー学会
  • Place of Presentation: 福岡
• [Remarks] 愛媛大学大学院医学系研究科免疫学・感染防御学ホームページ
  • URL: http://www.m.ehime-u.ac.jp/school/immunology/