Ludwig Institute for Cancer Research, University of Lausanne and Department of Oncology, Lausanne University Hospital (CHUV), Lausanne, Switzerland.
EMBO J. 2024 Nov;43(21):4922-4953. doi: 10.1038/s44318-024-00235-w. Epub 2024 Sep 16.
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.
CD8+T 细胞在肿瘤控制中起着关键作用，但它们微环境中的一系列因素，如低 pH 值，会抑制其功能。在这里，我们证明了酸度主要通过抑制 IL-2 反应性来限制 T 细胞的扩增，降低再激活时细胞因子的分泌，并降低表达低亲和力 TCR 的 CD8+T 细胞的细胞毒性。我们进一步发现低 pH 值时 mTORC1 信号活性和 c-Myc 水平降低。在机制上，核/细胞质酸化与 Rheb、Akt/TSC2/PRAS40、GATOR1 和 Lkb1/AMPK 无关的 mTORC1 抑制有关，而 c-Myc 水平下降是由于转录减少和蛋白酶体介导的降解水平升高。此外，还观察到细胞内谷氨酰胺、谷氨酸和天冬氨酸水平降低，脯氨酸水平升高，但对 mTORC1 信号或 c-Myc 水平没有明显影响。总的来说，我们认为，由于酸度对 CD8+T 细胞的广泛影响，需要进行多种干预才能恢复 T 细胞功能，除非有效控制细胞内 pH 值。
