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.
© 2024. The Author(s).

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.