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bioRxiv · 10.1101/2023.12.15.571931

Acidity-induced dysfunction of CD8+ T cells is characterized by impaired IL-2 responsiveness and perturbations to mTORC1 signaling and c-Myc levels

Vuillefroy de Silly, R.·Pericou, L.·Seijo, B.·Crespo, I.·Coukos, G.·Irving, M.
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Abstract

CD8+ T cells play a critical role in cancer control but a range of barriers in the tumor microenvironment, including low pH, can impair their function. Here, we demonstrate that acidity dampens T-cell expansion mainly due to impaired IL-2 responsiveness, blunts cytokine secretion upon re-activation, and lowers the cytolytic capacity of CD8+ T cells expressing weak affinity TCR. We further reveal and dissect defects in both mTORC1 activity and c-Myc accumulation at low pH, the latter of which is largely due to proteasome-mediated degradation. In addition, lower intracellular levels of glutamine, glutamate and aspartate as well as elevated proline were noted, with no apparent impact on mTORC1 or c-Myc. Overall, low pH disrupts diverse intracellular signaling pathways as well as nutrient uptake/processing by T cells and we conclude that unless intracellular pH can be restored, multiple interventions will be required to overcome acidity-induced dysfunction.

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Vuillefroy de Silly, R., Pericou, L., Seijo, B., Crespo, I., Coukos, G., Irving, M.. 2023-12-16. Acidity-induced dysfunction of CD8+ T cells is characterized by impaired IL-2 responsiveness and perturbations to mTORC1 signaling and c-Myc levels. https://doi.org/10.1101/2023.12.15.571931

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