Transforming growth factor-b-regulated mTOR activity preserves cellular metabolism to maintain long-term T cell responses in chronic infection
Transforming growth factor-b-regulated mTOR activity preserves cellular metabolism to maintain long-term T cell responses in chronic infection
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DOI：
10.1016/j.immuni.2021.06.007
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发表时间：
2021-08-10
期刊：
影响因子：
32.4
通讯作者：
Kallies, Axel
中科院分区：
文献类型：
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作者：
Gabriel, Sarah S.;Tsui, Carlson;Kallies, Axel
慢性病毒感染和肿瘤中的抗原特异性 CD8(+) T 细胞功能恶化，这一过程称为衰竭。耗尽的 T 细胞由耗尽 (Tpex) 细胞的前体维持，这些前体在不断产生耗尽的效应 (Tex) 细胞的同时进行自我更新。然而，Tpex 细胞如何维持其功能仍不清楚。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 细胞的代谢随着时间的推移而恶化。 Tpex 细胞表现出对 mTOR 激酶信号传导的早期抑制，但保留了响应抗原受体信号而激活该通路的能力。早期短暂的 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 可抑制耗竭 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存使 Tpex 细胞能够在慢性感染期间保留维持 T 细胞反应的长期功能。
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-beta 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.