抗原認識のシグナル変換機構

• 研究課題/領域番号: 12051101
• 研究種目: 特定領域研究
• 配分区分: 補助金
• 審査区分: 生物系
• 研究機関: 千葉大学
• 研究代表者: 斉藤 隆 千葉大学, 大学院・医学研究院, 教授 (50205655)
• 研究分担者: 渡邊 武 九州大学, 生体防御医学研究所, 教授 (40028684) ; 黒崎 知博 関西医科大学, 医学部, 教授 (50178125)
• 研究期間 (年度): 2000 – 2002
• 研究課題ステータス: 完了 (2002年度)
• 配分額: 28,500千円 (直接経費: 28,500千円); 2002年度: 7,900千円 (直接経費: 7,900千円); 2001年度: 8,100千円 (直接経費: 8,100千円); 2000年度: 12,500千円 (直接経費: 12,500千円)
• キーワード: シグナル変換機構 / 免疫シナプス / 抑制性アダプター分子 / BLNK / PLC活性化 / 遺伝子欠損マウス / アポトーシス / ヒスタミン受容体 / シグナル伝達 / 抗原受容体 / アダプター分子 / 負の制御 / 細胞骨格 / フォスファターゼ / BCAP / PLC-γ欠損マウス / LAT / プレB細胞 / Lyn欠損マウス / Gab-2 / CTLA-4

研究概要

本調整班では、リンパ球が抗原認識した後に、機能発現・細胞分化などの様々な運命決定に導くための細胞内でのシグナル伝達系への情報変換機構の解析をT・B細胞において解析する事を目指した。
1)ラフト局在分子CbpがEBP50-ERM-Actinと会合して細胞骨格系にアンカーし、ラフトの膜状での可動性を調節するシステムが存在し、免疫シナプス形成をも制御することを発見した。Gab2がTCRシグナル系ではフィードバック抑制を担うアダプター分子であり、フォスファターゼをLAT/ラフトにリクルートする事によって抑制する機構を明らかにした。また、CTLA-4は主要な抑制性co-stimulationレセプターとしてT細胞分化においても抑制活性を示すことを示唆した。
2)BCRシグナル伝達における重要なアダプター分子BLNKとBCAPをクローニングし、その機能解析を、欠損細胞と欠損マウスを作製して行った。その結果、BLNKがPLCγ2を活性化させる上でラフトにリクルートされることが重要で、活性化BLNKはPLCγ2,Btkと複合体を形成し、BtkによってPLCγ2はリン酸化されることを示した。一方、BCAPは、Sykによりリン酸化され、P13Kのラフトへのリクルートを助け、PLCγ2に直接会合して活性化に関与していることを示唆した。
3)BCRシグナルで誘導される未熟B細胞の細胞死に必要な新規蛋白iWH37を単離した。iWH37はBCR刺激によって発現が誘導され、Mt膜のVDAC、Bacと結合し、高発現させると膜電位の低下を引き起こすことが判明した。一方、ヒスタミン受容体シグナルによるリンパ球の制御を欠損マウスを作製・解析し、アレルギー反応の惹起のみならず、TCR,BCRシグナル伝達系で重要な正の制御およびTH1,Th2細胞分化の制御に重要な役割を果たしていることを明らかにした。

研究成果

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