Department of Microbiology and Immunology, The Peter Doherty Institute for Infection and Immunity, University of Melbourne, Melbourne, VIC, Australia.
Olivia Newton-John Cancer Research Institute, Heidelberg, VIC, Australia; The Walter and Eliza Hall Institute of Medical Research, Melbourne, VIC, Australia; Department of Medical Biology, University of Melbourne, Melbourne, VIC, Australia; School of Cancer Medicine, La Trobe University, Heidelberg, VIC, Australia.
Immunity. 2021 Aug 10;54(8):1698-1714.e5. doi: 10.1016/j.immuni.2021.06.007. Epub 2021 Jul 6.
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.
慢性病毒感染和肿瘤中的抗原特异性 CD8 T 细胞功能逐渐恶化，这一过程被称为衰竭。衰竭的 T 细胞由衰竭前体（Tpex）细胞维持，这些细胞在不断产生衰竭效应（Tex）细胞的同时自我更新。然而，目前尚不清楚 Tpex 细胞如何维持其功能。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逐渐恶化。Tpex 细胞表现出早期抑制 mTOR 激酶信号，但保留了在抗原受体信号下激活该途径的能力。早期短暂的 mTOR 抑制可改善长期 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，是 Tpex 细胞代谢和功能的关键决定因素。总的来说，我们证明了细胞代谢的保存使 Tpex 细胞能够保持长期功能，以在慢性感染期间维持 T 细胞反应。
