TOXは,腫瘍特異のT細胞の微分化の重要なレギュラーである
Andrew C Scott1,2, Friederike Dündar3,4, Paul Zumbo3,4
1Immunology Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
Nature
|June 18, 2019
まとめ
核因子TOXは腫瘍におけるT細胞枯渇を調節する. TOXを消去すると 抑制性受容体の高調が防止されるが 機能は回復しない
科学分野:
- 免疫学
- 分子生物学
- 癌 研究
背景:
- 腫瘍特異のCD8T細胞は機能不全を示し,効果細胞や記憶T細胞とは異なる状態である.
- T細胞枯渇の調節因子を理解することは,抗腫瘍免疫を改善するために極めて重要です.
研究 の 目的:
- 腫瘍特異性T細胞 (TST) の分化と機能障害の重要なレギュレータを特定する.
- 腫瘍の微小環境内のT細胞枯渇における核因子TOXの役割を明らかにする.
主な方法:
- 慢性ウイルス感染症による機能不全のTST細胞と枯渇したT細胞におけるTOX発現の分析.
- エフェクタ T 細胞における子宮外TOX発現に関する in vitro 実験.
- 腫瘍内のTST細胞の Tox の遺伝的消去
- 遺伝子発現,クロマチンアクセシビリティ,転写因子プロフィールの評価
主要な成果:
- TOXは機能不全のTST細胞で高度に発現し,慢性的なT細胞受容体刺激とNFATの活性化によって引き起こされます.
- 胎内外TOX発現はT細胞疲労の転写プログラムを誘発する.
- 毒素の消去は,疲労プログラムを取り消し,抑制性受容体のアップレギュレーションを防止し,TCF-1の発現を維持します.
- 毒素消去されたTST細胞は機能不全であり,免疫フェノタイプが枯渇していないにもかかわらず,腫瘍に持続することができません.
結論:
- TOXはT細胞疲労の重要な調節体であり,抑制受容体の上昇調節を媒介する.
- TOXによる阻害受容体の調節は,エフェクタ機能の喪失から切り離されている.
- TOX誘発性疲労プログラムは,T細胞の過剰刺激と活性化誘発性細胞死を癌のような慢性抗原被曝環境で防ぐことができるが,T細胞の持続性を損なう.
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