CRISPRスクリーンは,T細胞免疫の栄養素認証のための信号ハブを明らかにします
Lingyun Long1, Jun Wei1, Seon Ah Lim1
1Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN, USA.
Nature
|November 19, 2021
まとめ
栄養素は,ラパミシン複合体1 (mTORC1) のメカニズム的標的に影響することによって,適応免疫を調節する. この研究では,mTORC1のシグナル伝達を制御し,T細胞機能と免疫耐性を影響する,SEC31AとCCDC101のような重要なタンパク質を特定しました.
科学分野:
- 免疫学
- 細胞の代謝
- 分子生物学
背景:
- 栄養素は適応免疫の重要な調節因子です
- 環境からの栄養信号と免疫学的経路の統合,特にラパミシン複合体1 (mTORC1) 経路のメカニズム的な標的は,まだ完全に理解されていません.
- mTORC1は細胞代謝と免疫細胞機能の中央調節体である.
研究 の 目的:
- ネズミの調節性T細胞 (Treg) の栄養素および免疫受容体に依存するmTORC1シグナリングを制御する調節モジュールを特定する.
- 環境信号が免疫調節のために統合されるメカニズムを明らかにする.
- T細胞機能と免疫耐性における特定されたレギュレータの役割を理解する.
主な方法:
- マウスのT (Treg) 細胞における全ゲノムCRISPRスクリーニング
- タンパク質とタンパク質の相互作用のネットワーク分析
- マウスモデルにおけるT細胞のプリミング,抑制機能,炎症,抗腫瘍免疫を評価するインビボ試験.
主要な成果:
- SEC31Aは,GATOR2成分SEC13を安定させることでmTORC1の活性化を促進することが確認された.
- SEC31Aの喪失は,T細胞のプリミングとTreg抑制機能の低下をマウスで示した.
- SWI/ SNF複合体はCASTOR1の発現を制限し,mTORC1の活性化を高めることが判明した.
- CCDC101に関連したSAGA複合体はmTORC1を阻害し,栄養媒体の発現を制限し,T細胞の静止状態を維持する.
- トレグ細胞におけるCcdc101の特定の消去は,制御不能な炎症を引き起こしたが,抗腫瘍免疫を強めた.
結論:
- エピジェネティックおよび翻訳後のメカニズムは,免疫信号への反応として,栄養素トランスポーター,センサ,トランスデューサを通じてmTORC1の活動を調節する.
- SEC31A,SWI/SNF,SAGA複合体は,T細胞免疫と免疫耐性を調節する上で重要な役割を果たします.
- これらの栄養素感知経路を理解することは,T細胞免疫を認可し,免疫耐性を確立するために不可欠です.
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