Acidity suppresses CD8 + T-cell function by perturbing IL-2, mTORC1, and c-Myc signaling.

ABSTRACT: 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 asp

SUBMITTER: Vuillefroy de Silly R 

PROVIDER: S-EPMC11535206 | biostudies-literature | 2024 Nov

REPOSITORIES: biostudies-literature