Systemic Biology of T cell differentiation

• Project/Area Number: 25670234
• Research Category: Grant-in-Aid for Challenging Exploratory Research
• Allocation Type: Multi-year Fund
• Research Field: Immunology
• Research Institution: Keio University
• Principal Investigator: YOSHIMURA Akihiko 慶應義塾大学, 医学部, 教授 (90182815)
• Co-Investigator(Renkei-kenkyūsha): YAMADA Satoshi 岡山理科大学, 工学部, 教授 (20393506)
• Project Period (FY): 2013-04-01 – 2015-03-31
• Project Status: Completed (Fiscal Year 2014)
• Budget Amount: ¥3,900,000 (Direct Cost: ¥3,000,000、Indirect Cost: ¥900,000); Fiscal Year 2014: ¥2,470,000 (Direct Cost: ¥1,900,000、Indirect Cost: ¥570,000); Fiscal Year 2013: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
• Keywords: サイトカイン / シグナル伝達 / 転写因子 / ヘルパーT細胞 / 制御性T細胞 / TGFβ / モデル化 / エピジェネティクス / 遺伝子発現制御

Outline of Final Research Achievements

Helper T cells have been thought to play a central role in not only acquired immune responses but also in immune regulation. Recently, several subsets such as Th9, Th17 and iTreg have been discovered in addition to Th1 and Th2. Differentiation of each helper T cell subset is extremely complicated. Thus, we have tried to define the mechanism of helper T cell differentiation by focusing on TGF-beta signaling. We discovered Th9 differentiation by TGF-beta and IL-4 is Smad2/3 dependent and required for IRF4 transcription factor. We also found that TGF-beta from dendritic cells plays important role in iTreg differentiation in the gut. We showed that the TLR2-AP-1 pathway as well as the Smad3 pathway are critical for TGF-beta production by intestinal microflora.

Research Products

• [Journal Article] Bruton's tyrosine kinase is an essential component for NLRP3 inflammasome activation and a potential therapeutic target for ischemic brain injury (2015)
  • Author(s): Ito M, Shichita T, Morita R, Yoshimura A
  • Journal Title: Nature Communications Volume: 未定
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] A gp130-Src-YAP module links inflammation to epithelial regeneration. (2015)
  • Author(s): Taniguchi K, Wu LW, Grivennikov SI, de Jong PR, Lian I, Yu FX, Wang K, Ho SB, Boland BS, Chang JT, Sandborn WJ, Hardiman G, Raz E, Maehara Y, Yoshimura A, Zucman-Rossi J, Guan KL, Karin M.
  • Journal Title: Nature Volume: 519 Issue: 7541 Pages: 57-62
  • DOI: 10.1038/nature14228
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] ETS transcription factor ETV2 directly converts human fibroblasts into functional endothelial cells. (2015)
  • Author(s): Morita R, Suzuki M, Kasahara H, Shimizu N, Shichita T, Sekiya T, Kimura A, Sasaki K, Yasukawa H, Yoshimura A.
  • Journal Title: Proc Natl Acad Sci U S A. Volume: 112 Issue: 1 Pages: 160-165
  • DOI: 10.1073/pnas.1413234112
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Prevention of allogeneic cardiac graft rejection by transfer of ex vivo expanded antigen-specific regulatory T-cells. (2014)
  • Author(s): Takasato F, Morita R, Schichita T, Sekiya T, Morikawa Y, Kuroda T, Niimi M, Yoshimura A.
  • Journal Title: PLoS One. Volume: 9(2) Issue: 2 Pages: e87722-e87722
  • DOI: 10.1371/journal.pone.0087722
  • Peer Reviewed / Open Access
• [Journal Article] Aryl hydrocarbon receptor protects against bacterial infection by promoting macrophage survival and reactive oxygen species production (2014)
  • Author(s): Kimura A, Abe H, Tsuruta S, Chiba S, Fujii-Kuriyama Y, Sekiya T, Morita R, Yoshimura A.
  • Journal Title: Int Immunol. Volume: 26 Issue: 4 Pages: 209-220
  • DOI: 10.1093/intimm/dxt067
  • Peer Reviewed / Open Access
• [Journal Article] Aryl hydrocarbon receptor plays protective roles in ConA-induced hepatic injury by both suppressing IFN-Y expression and inducing IL-22 (2014)
  • Author(s): Abe H, Kimura A, Tsuruta S, Fukaya T, Sakaguchi R, et al.
  • Journal Title: Int Immunol. Volume: 26 Issue: 3 Pages: 129-137
  • DOI: 10.1093/intimm/dxt049
  • Peer Reviewed / Open Access
• [Journal Article] TRAF6 Is Essential for Maintenance of Regulatory T Cells That Suppress Th2 Type Autoimmunity. (2013)
  • Author(s): Muto G, Kotani H, Kondo T, Morita R, Tsuruta S, Kobayashi, T., Luche H, Fehling HJ, Walsh M, Choi Y, Yoshimura A.
  • Journal Title: PLoS One Volume: 8 (9) Issue: 9 Pages: e74639-e74639
  • DOI: 10.1371/journal.pone.0074639
  • Peer Reviewed
• [Presentation] Molecular Basis for the Post-Ischemic Inflammation in the Brain (2014)
  • Author(s): Akihiko Yoshimura, Minako Ito, Masahiro Okada, and Takashi Shichita
  • Organizer: The 12th International Congress of Neuroimmunology
  • Place of Presentation: Mainz, Germany
  • Year and Date: 2014-11-09 – 2014-11-13
  • Invited
• [Presentation] Molecular basis for the induction of regulatory T cells by gram-positive bacteria and TGF-beta in the intestine (2014)
  • Author(s): Yoshimura A, Okada M, and Kashiwagi
  • Organizer: Recent Advances in Immunology and Inflammation
  • Place of Presentation: Fukuoka
  • Year and Date: 2014-11-07 – 2014-11-08
  • Invited
• [Presentation] Treg induction by gram-positive bacterium Clostridium Butylicum in the intestine is medaited by TLR2- and Smad3-dependent TGF-be-ta1 production in dendritic cells (2014)
  • Author(s): Akihiko Yoshimura, Ikko Kashiwagi
  • Organizer: The Fourth International Conference on Regulatory T Cells and Th Subsets and Clinical Application in Human Diseases
  • Place of Presentation: Shanghai, China.
  • Year and Date: 2014-11-01 – 2014-11-04
  • Invited
• [Presentation] 腸内細菌による食物アレルギーおよび Treg の制御 (2014)
  • Author(s): 吉村昭彦
  • Organizer: 第35回日本炎症・再生医学会総会
  • Place of Presentation: 沖縄・万国津梁館
  • Year and Date: 2014-07-01 – 2014-07-04
  • Invited
• [Presentation] リウマチのコンピュータモデル (2013)
  • Author(s): 山田訓、吉村昭彦
  • Organizer: 第３６回日本分子生物学会 年会
  • Place of Presentation: 神戸
• [Presentation] Computer model of rheumatoid arthritis (2013)
  • Author(s): Satoshi Yamada, Akihiko Yoshimura
  • Organizer: 第４２回日本免疫学会学術集会
  • Place of Presentation: 幕張メッセ （千葉市）