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アルファベータT細胞受容体のモチーフは,ERKの活性を調節することによって,陽性選択を制御する
G Werlen1, B Hausmann, E Palmer
1Basel Institute for Immunology, Switzerland. werlen@bii.ch
Nature
|August 10, 2000
まとめ
胸腺におけるポジティブな選択には,特定のT細胞受容体 (TCR) 信号伝達が必要である. 変異したTCRアルファ鎖モチーフは,陽性選択に不可欠な細胞外信号調節キナーゼ (ERK) の活性化を損なう.
科学分野:
- 免疫学 免疫学とは
- 分子生物学は分子生物学である.
- 細胞シグナル伝達 細胞信号伝達
背景:
- ポジティブとネガティブな選択を含む胸膜の選択は,T細胞の発達に不可欠です.
- この2つのプロセスは,アルファベタT細胞受容体 (TCR) と自己メジャーヒストコンパティビリティ複合体 (自己MHC) の認識を伴う.
- 明確なシグナル伝達経路は,ポジティブ対ネガティブな選択を制御する可能性があります.
研究 の 目的:
- 異なるシグナリングカスケードがポジティブとネガティブの胸膜選択を調節するかどうかを調査する.
- ミトゲン活性化タンパク質キナーゼ (MAPK) のカスケードがタイミック選択における役割を決定する.
- TCRによるポジティブな選択のためのシグナリング要件を明らかにする.
主な方法:
- 変異したTCRアルファ鎖結合ペプチドメイン (alpha-CPM) 受容体を発現する変異性マウスを利用した.
- 細胞外信号調節キナーゼ (ERK) を含む様々なMAPKカスケードの活性化を調べました.
- Lck,ZAP-70,CD3zeta,LATのようなシグナル伝達分子が,洗剤不溶性グリコリピド濃縮マイクロドメイン (DIG) に誘導される様子を評価した.
主要な成果:
- TCRのα-CPMモチーフの突然変異は,選択的にポジティブな選択を妨げました.
- 陽性選択ペプチドは,変異したTCRを持つチモサイトでERKを活性化することができなかった.
- この欠陥は,Lck,ZAP-70,CD3zeta,およびLATのDIGへのリクルートが減少したことと相関していた.
結論:
- 健全なDIG関連シグナルソームに依存する持続的なERK活性化は,陽性の胸膜選択に不可欠です.
- この発見は,ERKシグナリングが,ネガティブな選択経路とは異なる,ポジティブな選択における特定の役割を示唆している.
- これは,TCR媒介の胸膜教育のためのDIG内のシグナル分子の区画化の重要性を強調しています.
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