Negative selection of T cells by the factor suppressing autoimmunity

• Project/Area Number: 16H06228
• Research Category: Grant-in-Aid for Young Scientists (A)
• Allocation Type: Single-year Grants
• Research Field: Experimental pathology
• Research Institution: The University of Tokyo
• Principal Investigator: Takaba Hiroyuki 東京大学, 大学院医学系研究科(医学部), 助教 (50637444)
• Research Collaborator: Takayanagi hiroshi
• Project Period (FY): 2016-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥23,660,000 (Direct Cost: ¥18,200,000、Indirect Cost: ¥5,460,000); Fiscal Year 2018: ¥6,500,000 (Direct Cost: ¥5,000,000、Indirect Cost: ¥1,500,000); Fiscal Year 2017: ¥7,280,000 (Direct Cost: ¥5,600,000、Indirect Cost: ¥1,680,000); Fiscal Year 2016: ¥9,880,000 (Direct Cost: ¥7,600,000、Indirect Cost: ¥2,280,000)
• Keywords: 免疫寛容 / 獲得免疫 / T細胞 / 中枢免疫寛容 / 中枢寛容 / 自己免疫 / T細胞の選択

Outline of Final Research Achievements

T cells are one of the most important population for adaptive immune system. It is well known that T cells are generated in the thymus and the autoantigens are produced by medullary thymic epithelial cells expressing two transcriptional regulators Aire and Fezf2. In this study, we characterized the distinct features of Fezf2-dependent and Aire-dependent genes expressed in mTECs. Single cell RNA-seq analysis revealed the different expression pattern between Aire-dependent and Fezf2-dependent genes among mTECs. Our study suggest that the expression level of autoantigens might be key for the negative selection of T cells and regulatory T cell differentiation in the thymus to establish immune tolerance.

Academic Significance and Societal Importance of the Research Achievements

免疫寛容の破綻は、自己免疫疾患やアレルギー疾患を引き起こし、日常生活に大きな支障をきたす。自己免疫疾患の患者は、日本国内だけでも数百万人いると見積もられている。免疫疾患の患者数は年々増加の一途を辿り、社会的にも深刻な問題であり、根本的な治療法の確立が喫緊の課題である。自己抗原が特定されていない自己免疫疾患は多くあり、自己抗原を認識するT細胞の集団とその抗原を同定することは自己免疫疾患の根本的治療に関わる。自己抗原は胸腺内でストローマ細胞のmTECで主に発現しており、この分子基盤の解明が将来的に自己免疫の効率的な治療法の開発に繋がる。

Research Products

• [Int'l Joint Research] MIT(米国)
• [Journal Article] The mechanisms of T cell selection in the thymus (2017)
  • Author(s): Hiroyuki Takaba and Hiroshi Takayanagi
  • Journal Title: Trends in immunology Volume: 38, 11 Issue: 11 Pages: 805-8016
  • DOI: 10.1016/j.it.2017.07.010
  • NAID: 40021132352
  • Peer Reviewed / Open Access
• [Presentation] Self-Reflection by Tolerogenic Factors: Promiscuous Gene Expression in the Thymus (2018)
  • Author(s): Hiroyuki Takaba
  • Organizer: Japanese Society for Immunology(JSI)
  • Invited
• [Presentation] Epigenetic regulation of thymic self-antigen expression for immune tolerance (2018)
  • Author(s): Hiroyuki Takaba, Yoshihiko Tomofuji, Hiroshi Takayanagi
  • Organizer: Gordon conference
  • Int'l Joint Research
• [Presentation] Distinct features of Fezf2-dependent promiscuous gene expression (2018)
  • Author(s): Yoshihiko Tomofuji, Hiroyuki Takaba and Hiroshi Takayanagi
  • Organizer: ThymOZ8
  • Int'l Joint Research
• [Presentation] T cell selection mediated by Fezf2 in the thymus (2017)
  • Author(s): Hiroyuki Takaba and Hiroshi Takayanagi
  • Organizer: KTCC 2017
  • Place of Presentation: Kyoto, Japan
  • Year and Date: 2017-03-14
  • Int'l Joint Research
• [Presentation] 免疫学のセントラルドグマ (2017)
  • Author(s): 高場啓之
  • Organizer: Conbio2017
  • Invited
• [Book] 胸腺におけるT細胞の選択機構 (2017)
  • Author(s): 高場啓之、高柳広
  • Total Pages: 6
  • Publisher: 臨床免疫・アレルギー科