澳大利亚墨尔本大学Axel Kallies、Daniel T. Utzschneider等研究人员合作发现，转化生长因子β调节的mTOR活性通过控制细胞代谢来维持慢性感染中的长期T细胞应答。2021年7月6日，《免疫》杂志在线发表了这一最新研究成果。

研究人员表示，慢性病毒感染和肿瘤的抗原特异性CD8⁺T细胞功能恶化，一种称为耗竭的过程。耗竭的T细胞由耗竭的（Tpex）细胞的前体来维持，其在连续产生耗竭效应子（Tex）细胞的同时自我更新。但是，Tpex细胞如何维持其功能仍然未知。

研究人员证明，Tpex细胞能够维持线粒体健康，包括高保留的呼吸能力，而Tex细胞随着时间的推移代谢恶化。Tpex细胞显示出mTOR激酶信号的早期抑制，但保留响应于抗原受体信号而激活该途径的能力。早期瞬时mTOR抑制改善了长期T细胞应答和检查点抑制。耗竭T细胞中的转换生长因子β抑制mTOR信号传导，这是Tpex细胞代谢和功能的关键决定因素。

总的来说，研究人员证明了细胞代谢的维持允许Tpex细胞保留长期功能，从而在慢性感染期间维持T细胞应答。

附：英文原文

Title: Transforming growth factor-β-regulated mTOR activity preserves cellular metabolism to maintain long-term T cell responses in chronic infection

Author: Sarah S. Gabriel, Carlson Tsui, David Chisanga, Flora Weber, Manuela Llano-León, Patrick M. Gubser, Laurent Bartholin, Fernando Souza-Fonseca-Guimaraes, Nicholas D. Huntington, Wei Shi, Daniel T. Utzschneider, Axel Kallies

Issue&Volume: 2021-07-06

Abstract: Antigen-specific CD8+ T cells in chronic viral infections and tumors functionally deteriorate, a processknown 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, wedemonstrate that Tpex cells sustained mitochondrial fitness, including high sparerespiratory capacity, while Tex cells deteriorated metabolically over time. Tpex cellsshowed early suppression of mTOR kinase signaling but retained the ability to activatethis pathway in response to antigen receptor signals. Early transient mTOR inhibitionimproved long-term T cell responses and checkpoint inhibition. Transforming growthfactor-β repressed mTOR signaling in exhausted T cells and was a critical determinantof Tpex cell metabolism and function. Overall, we demonstrate that the preservationof cellular metabolism allows Tpex cells to retain long-term functionality to sustainT cell responses during chronic infection.

DOI: 10.1016/j.immuni.2021.06.007

Source: https://www.cell.com/immunity/fulltext/S1074-7613(21)00251-X