CD8 + T cells have critical roles in tumor control, but a range of factors in their microenvironment such as low pH can suppress their function. Here, we demonstrate that acidity restricts T-cell expansion mainly through impairing IL-2 responsiveness, lowers cytokine secretion upon re-activation, and reduces the cytolytic capacity of CD8 + T cells expressing low-affinity TCR. We further find decreased mTORC1 signaling activity and c-Myc levels at low pH. Mechanistically, nuclear/cytoplasmic acidification is linked to mTORC1 suppression in a Rheb-, Akt/TSC2/PRAS40-, GATOR1- and Lkb1/AMPK-independent manner, while c-Myc levels drop due to both decreased transcription and higher levels of proteasome-mediated degradation. In addition, lower intracellular levels of glutamine, glutamate, and aspartate, as well as elevated proline levels are observed with no apparent impact on mTORC1 signaling or c-Myc levels. Overall, we suggest that, due to the broad impact of acidity on CD8 + T cells, multiple interventions will be required to restore T-cell function unless intracellular pH is effectively controlled.

中文翻译：

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酸性通过扰乱 IL-2、mTORC1 和 c-Myc 信号传导来抑制 CD8 + T 细胞功能。


CD8 + T 细胞在肿瘤控制中起关键作用，但其微环境中的一系列因素（如低 pH 值）会抑制其功能。在这里，我们证明酸性主要通过损害 IL-2 反应性来限制 T 细胞扩增，降低再激活时的细胞因子分泌，并降低表达低亲和力 TCR 的 CD8 + T 细胞的溶细胞能力。我们进一步发现在低 pH 值下 mTORC1 信号活性和 c-Myc 水平降低。从机制上讲，核/细胞质酸化以 Rheb-、Akt/TSC2/PRAS40-、GATOR1 和 Lkb1/AMPK 非依赖性方式与 mTORC1 抑制有关，而 c-Myc 水平由于转录减少和蛋白酶体介导的降解水平较高而下降。此外，观察到谷氨酰胺、谷氨酸和天冬氨酸的细胞内水平较低，脯氨酸水平升高，对 mTORC1 信号转导或 c-Myc 水平没有明显影响。总体而言，我们认为，由于酸度对 CD8 + T 细胞的广泛影响，除非细胞内 pH 值得到有效控制，否则需要多种干预来恢复 T 细胞功能。