Functional analysis of autoimmune-associating phosphatases in T cell

• Project/Area Number: 16K08851
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Immunology
• Research Institution: Institute of Physical and Chemical Research
• Principal Investigator: Hashimoto-tane Akiko 国立研究開発法人理化学研究所, 生命医科学研究センター, 上級研究員 (10415226)
• Project Period (FY): 2016-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000); Fiscal Year 2018: ¥650,000 (Direct Cost: ¥500,000、Indirect Cost: ¥150,000); Fiscal Year 2017: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000); Fiscal Year 2016: ¥2,470,000 (Direct Cost: ¥1,900,000、Indirect Cost: ¥570,000)
• Keywords: 自己免疫性疾患 / 抗原受容体シグナル / 脱リン酸化酵素 / 蛍光イメージング / T細胞 / 受容体シグナル / GWAS / 自己免疫 / T細胞受容体シグナル / T細胞受容体 / ネガティブフィードバック / 基礎医学 / 免疫学

Outline of Final Research Achievements

GWAS study demonstrated that two tyrosine phosphatases (PTPN22 and PTPN2) had high association with autoimmune-diseases; type I diabetes, Rheumatoid arthritis etc,. I analyzed the molecular functions of these phosphatases in T cell.
PTPN22 works for stopping immune responses. In T cells, PTPN22 made molecular complex with other inhibitory molecules and reduced the sensitivity of T cell for foreign materials. The SNPs mutant product(R619W)of PTPN22 failed to make the complex and resulted in T cell hyper responsiveness and higher susceptibility for autoimmune-diseases. PTPN2 also works on stopping immune responses by regulating gene expressions. The reduction of PTPN2 by nucleotide polymorphism increased expressions of many kinds of inflammatory cytokines and chemokines. As a result, even small inflammation would be enhanced and would be followed by autoimmune-responses.

Academic Significance and Societal Importance of the Research Achievements

近年のゲノム関連解析は多種多様なBig dataを与えているが、統計データには裏付けとなる生物学的な証拠が必要である。遺伝子の変異箇所はわかっても、変異による分子細胞レベルの変化を知らなければ治療や予防に役立てることは難しい。
本研究ではゲノム解析で自己免疫性疾患(I型糖尿病、関節リウマチ)に関連した２つの脱リン酸化酵素の細胞内分子機能を明らかにした。この結果は治療や予防の方針決定に貢献できる。例えばPTPN22にSNPsがある場合はT細胞受容体の阻害、異物との接触回避などが効果的で、PTPN2にSNPsがある場合は転写を抑える方法が効果的だと考えられる。よって学術および臨床的に意義深い。

Research Products

• [Journal Article] Inhibition of T cell activation and function by the adaptor protein CIN85. (2019)
  • Author(s): Kong Mei S*., Hashimoto-Tane A*., Kawashima Y., Sakuma M., Yokosuka T., Kometani K., Onishi R., Carpino N., Ohara O., Kurosaki T., Phua K.K. and Saito, T.
  • Journal Title: Sci Signal Volume: 12 Pages: 1609-1625
  • DOI: 10.1126/scisignal.aav4373
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Analyzing the Dynamics of Signaling Microclusters (2017)
  • Author(s): Hashimoto-Tane A, Yokosuka T, Saito T.
  • Journal Title: Methods Mol. Biol. Volume: 1584 Pages: 5-64
  • DOI: 10.1007/978-1-4939-6881-7_4
  • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] TCRマイクロクラスター，マイクロリングと T 細胞活性化 (2017)
  • Author(s): 多根(橋本)彰子
  • Journal Title: 臨床免疫・アレルギー科 Volume: 67(3) Pages: 295-301
• [Journal Article] Micro-adhesion rings surrounding TCR microclusters are essential for T cell activation (2016)
  • Author(s): Hashimoto-Tane A, Sakuma M, Ike H, Yokosuka T, Kimura Y, Ohara O, Saito T.
  • Journal Title: The Journal of Experimental Medicine Volume: 213 Pages: 1609-1625
  • DOI: 10.1084/jem.20151088
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Dynamic regulation of TCR-microclusters and the microsynapse for T cell activation. (2016)
  • Author(s): Hashimoto-Tane A., Saito T.
  • Journal Title: Frontiers Immunology Volume: 7(255) Pages: 1-8
  • DOI: 10.3389/fimmu.2016.00255
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Presentation] Molecular assembly and function of PTPN22 in T cell receptor signaling (2018)
  • Author(s): Akiko Hashimoto-tane
  • Organizer: FASEB Immunoreceptors and Immunotherapy
  • Int'l Joint Research
• [Presentation] Functional analysis of autoimmune-associated phosphatase PTPN2(TCPTP) in T cells (2018)
  • Author(s): Akiko Hashimoto-tane
  • Organizer: 2018 Annual Meeting of Japanese Society for Immunology
• [Presentation] Function of autoimmune-related phosphatase PTPN22 in T cell signaling (2017)
  • Author(s): HASHIMOTO-TANE Akiko, Takashi Saito
  • Organizer: 日本薬理学会年会
  • Place of Presentation: 長崎ブリックホール(長崎県長崎市)
  • Year and Date: 2017-03-15
• [Presentation] Molecular assembly and function of PTPN22 in T cell receptor signaling (2017)
  • Author(s): Akiko Hashimoto-Tane and Takashi Saito
  • Organizer: 2017 Annual Meeting of Japanese Society for Immunology
• [Presentation] Function of autoimmune-related phosphatase PTPN22 in T cell signaling (2016)
  • Author(s): HASHIMOTO-TANE Akiko, Takashi Saito
  • Organizer: 2016 Annual Meeting of the Japanese Society for Immunology
  • Place of Presentation: 沖縄コンベンションセンター(沖縄県宜野湾市)
  • Year and Date: 2016-12-05
• [Presentation] Micro adhesion rings surrounding TCR microclusters are essential for T cell activation (2016)
  • Author(s): HASHIMOTO-TANE Akiko, Takashi Saito
  • Organizer: EMBO conference
  • Place of Presentation: イタリア、シエナ
  • Year and Date: 2016-09-03
  • Int'l Joint Research