Functional analysis of autoimmune-associating phosphatases in T cell

2018 Fiscal Year Final Research Report

• 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 (橋本彰子) 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
• 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

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.

Free Research Field

免疫学

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。