調節性T細胞のCRISPRスクリーンで,Foxp3の調節物質が検出される
Jessica T Cortez1,2,3,4, Elena Montauti5, Eric Shifrut2,3,4
1Biomedical Sciences Graduate Program, University of California, San Francisco, CA, USA.
Nature
|June 6, 2020
まとめ
研究者らは,T (Treg) 細胞の調節に不可欠なタンパク質であるFoxp3の重要な調節体を特定した. Usp22はFoxp3を安定させ,Rnf20は不安定化させ,がんや自己免疫疾患の免疫療法に新たな標的を提供している.
科学分野:
- 免疫学
- 分子生物学
- 遺伝学
背景:
- 調節性T細胞は免疫ホメオスタシスに不可欠ですが,抗腫瘍免疫を阻害します.
- Foxp3の喪失によって特徴づけられるTregの不安定さは,自己免疫を誘発したり,抗腫瘍反応を強めたりします.
- Foxp3の調節を理解することは,がんや自己免疫疾患に対するTregベースの治療法の開発に不可欠です.
研究 の 目的:
- 主要なマウスTreg細胞におけるFoxp3発現を制御する遺伝子調節プログラムを特定する.
- ガンや自己免疫疾患におけるTreg細胞機能を調節する新しい標的を発見する.
主な方法:
- CRISPRベースのTreg細胞現象型のプールのスクリーニングプラットフォームを開発しました.
- 約500の核因子の標的型機能喪失スクリーンを実行した.
- Treg細胞の機能と安定性におけるUsp22とRnf20の役割を調査した.
主要な成果:
- ユビキチン固有のペプチダゼ22 (Usp22) が,Foxp3発現を安定させる陽性調節剤として特定された.
- Foxp3発現の負の調節体として指輪指タンパク質20 (Rnf20) を特定した.
- トレグ特異のUsp22除去は,自己免疫と抗腫瘍免疫の低下をもたらし,Rnf20除去によって救出され,相互のユビキチンスイッチを示した.
結論:
- Foxp3,Usp22およびRnf20の新しい調節剤を発見し,ユビキチンベースの調節メカニズムを強調した.
- 主要なTreg細胞における機能的ゲノミクスのための強力なCRISPRスクリーニングプラットフォームを実証した.
- これらの発見は,がんや自己免疫疾患に対するTreg免疫療法の開発のための新しいターゲットを提供します.
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