抗腫瘍免疫におけるT細胞活性化の抑制

• Project/Area Number: 09256202
• Research Category: Grant-in-Aid for Scientific Research on Priority Areas (A)
• Allocation Type: Single-year Grants
• Research Institution: Chiba University
• Principal Investigator: 斉藤 隆 千葉大学, 大学院・医学研究科, 教授 (50205655)
• Co-Investigator(Kenkyū-buntansha): 山崎 晶 千葉大学, 大学院・医学研究科, 助手 (40312946) ; 荒瀬 尚 千葉大学, 医学部, 助手 (10261900) ; 大野 博司 千葉大学, 医学部, 助教授 (50233226)
• Project Period (FY): 1997 – 1999
• Project Status: Completed (Fiscal Year 1999)
• Budget Amount: ¥51,000,000 (Direct Cost: ¥51,000,000); Fiscal Year 1999: ¥18,000,000 (Direct Cost: ¥18,000,000); Fiscal Year 1998: ¥18,000,000 (Direct Cost: ¥18,000,000); Fiscal Year 1997: ¥15,000,000 (Direct Cost: ¥15,000,000)
• Keywords: 抗腫瘍免疫 / T細胞 / ネガティブシグナル / CTLA-4 / リソソーム / Gab-2 / SHP-2 / チロシリン酸化 / シグナル伝達機構 / Jak3 / 抑制性シグナル / チロシンモチーフ / Co-stimulation / アダプター複合体 / μ2 / チロシンリン酸化 / internalization

Research Abstract

抗腫瘍免疫を賦活するために、抗腫瘍免疫を中心的に担うT細胞の活性化機構を明らかにすることを目的とし、その中でもとりわけ、T細胞の活性化をネガティブに抑制しているシグナル伝達機構を解明し、その人為的制御を目指した。そのために、1.昨年に引き続き、活性化をネガティブに抑制するCTLA-4分子のT細胞での発現調節とネガティブシグナルの誘導機構を解明する、2.SHP-2結合分子Gab-2のT細胞における役割を明らかにする、ための解析を進め、以下の点を明らかにした。
抑制シグナルを誘導するCTLA-4はCD4+T細胞においては、細胞内のリソソームに存在し、活性化されない場合には短期間で分解されることが判明した。TCR刺激に伴って、CTLA-4を含むリソソームは細胞膜に近づき、CTLA-4は細胞表面発現を亢進する。この際、同時にリソソームマーカーも発現し特異的酵素が分泌されることから、分泌型リソソームが細胞膜と融合することによってCTLA-4の細胞表面の発現が調節されていることを明らかにした。
IRS-1ファミリーのGab-2は、TCR刺激においてもリン酸化され、T細胞活性化に伴って、TCRシグナル伝達に重要な分子、ZAP-70,SLP-76,LAT,CD3zなどと会合する。Gab-2はZAP-70によってリン酸化され、C末端のチロシンを介してSHP-2と会合する。Gab-2はTCR刺激に伴うNFATの活性化やIL-2産生を抑制するが、SHP-2と会合できない変異Gab-2は抑制活性がないことから、Gab-2はTCR活性化に伴ってSHP-2をリクルートして活性化抑制を行なうことを明らかにした。

Research Products

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