Antigen-specific CD8⁺ T cells in chronic viral infections and tumors functionally deteriorate, a process known as exhaustion. Exhausted T cells are sustained by precursors of exhausted (Tpex) cells that self-renew while continuously generating exhausted effector (Tex) cells. However, it remains unknown how Tpex cells maintain their functionality. Here, we demonstrate that Tpex cells sustained mitochondrial fitness, including high spare respiratory capacity, while Tex cells deteriorated metabolically over time. Tpex cells showed early suppression of mTOR kinase signaling but retained the ability to activate this pathway in response to antigen receptor signals. Early transient mTOR inhibition improved long-term T cell responses and checkpoint inhibition. Transforming growth factor-β repressed mTOR signaling in exhausted T cells and was a critical determinant of Tpex cell metabolism and function. Overall, we demonstrate that the preservation of cellular metabolism allows Tpex cells to retain long-term functionality to sustain T cell responses during chronic infection.

抗原特异性 CD8 ⁺慢性病毒感染和肿瘤中的 T 细胞功能恶化，这一过程称为衰竭。耗竭的 T 细胞由耗竭 (Tpex) 细胞的前体维持，这些细胞在不断产生耗竭效应 (Tex) 细胞的同时进行自我更新。然而，Tpex 细胞如何保持其功能仍然未知。在这里，我们证明 Tpex 细胞维持线粒体健康，包括高备用呼吸能力，而 Tex 细胞随着时间的推移代谢恶化。Tpex 细胞显示出 mTOR 激酶信号传导的早期抑制，但保留了响应抗原受体信号激活该途径的能力。早期瞬时 mTOR 抑制改善了长期 T 细胞反应和检查点抑制。转化生长因子-β 抑制衰竭 T 细胞中的 mTOR 信号传导，并且是 Tpex 细胞代谢和功能的关键决定因素。总体而言，我们证明细胞代谢的保持允许 Tpex 细胞保留长期功能，以在慢性感染期间维持 T 细胞反应。