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Updated: Jan 7, 2026

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組織常駐疲弊および記憶CD8+ T細胞は、疾患における異なる起源、機能、および役割を持つ

Simone L Park^1,2, Mark M Painter^3,4, Sasikanth Manne^3,4

¹Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. simone.park@pennmedicine.upenn.edu.

Nature immunology

|December 30, 2025

Insights

慢性抗原刺激は、記憶（T_RM）細胞とは異なる、組織常駐疲弊CD8+ T（TR-T_EX）細胞を生成する。TR-T_EX細胞は、患者における免疫チェックポイント阻害応答を特異的に予測する。

科学分野:

免疫学; 細胞生物学; 慢性疾患病因学

背景:

常駐および疲弊マーカーを共発現するCD8+ T細胞は、慢性疾患の転帰と関連している。; これらの細胞、従来の組織常駐記憶（T_RM）細胞、および疲弊CD8+ T（T_EX）細胞との正確な関係は未定義のままである。

研究の目的:

慢性抗原曝露設定における組織常駐疲弊T_EX（TR-T_EX）細胞とT_RM細胞の異なる発生経路と機能的役割を解明すること。; 免疫チェックポイント阻害療法におけるTR-T_EX細胞の転写調節と治療的可能性を調査すること。

主な方法:

慢性抗原刺激と抗原クリアランス下でのT細胞集団の比較分析。; Tox依存性を含む細胞状態特異的調節ネットワークを特定するための転写プロファイリング。; PD-1経路阻害に対するT細胞応答を評価するinvivo研究。

主要な成果:

慢性抗原刺激は、T_RM細胞とは転写的に異なるTR-T_EX細胞を生成し、それらは常駐プログラミングにToxを必要とする。; T_RM細胞は慢性抗原曝露下でT_EX細胞に分化できるが、抗原除去後T_EX細胞はT_RM細胞に回復しない。; TR-T_EX細胞の存在は、患者の免疫チェックポイント阻害への応答と選択的に相関し、これらの細胞（T_RM細胞ではない）がinvivoでPD-1阻害に応答する。

結論:

TR-T_EX細胞とT_RM細胞は、組織常駐を共有するが慢性疾患中の機能が異なる、発生的に分岐したCD8+ T細胞状態を表す。; TR-T_EX細胞は疾患制御における主要な役割を果たし、免疫チェックポイント阻害の潜在的なバイオマーカーおよび治療標的を表す。

Read full analysis

Abstract:

The presence of CD8⁺ T cells coexpressing residency and exhaustion molecules in chronic diseases often correlate with clinical outcomes; however, the relationship between these cells and conventional tissue-resident memory (T_RM) cells or exhausted CD8⁺ T (T_EX) cells is unclear. Here we show that chronic antigen stimulation drives development of tissue-resident T_EX (TR-T_EX) cells that are distinct from T_RM cells generated after antigen clearance. TR-T_EX and T_RM cells are regulated by different transcriptional networks with only TR-T_EX cells being Tox-dependent for residency programming. While T_EX cells (including TR-T_EX) are unable to generate T_RM cells after antigen withdrawal, T_RM cells differentiate into T_EX cells upon chronic antigen exposure. Cell-state-specific transcriptional signatures reveal a selective association of TR-T_EX cells with patient responses to immune checkpoint blockade, and only TR-T_EX but not T_RM cells responded to PD-1 pathway inhibition in vivo. These data suggest that TR-T_EX and T_RM cells are developmentally divergent cell states that share a tissue-residency program but have distinct roles in disease control.

キーワード:

組織常駐疲弊T細胞組織常駐記憶T細胞 CD8+ T細胞慢性抗原刺激免疫チェックポイント阻害

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