Acidity suppresses CD8 + T-cell function by perturbing IL-2, mTORC1, and c-Myc signaling.
Détails
ID Serval
serval:BIB_D12C9C14E19B
Type
Article: article d'un périodique ou d'un magazine.
Collection
Publications
Institution
Titre
Acidity suppresses CD8 + T-cell function by perturbing IL-2, mTORC1, and c-Myc signaling.
Périodique
The EMBO journal
ISSN
1460-2075 (Electronic)
ISSN-L
0261-4189
Statut éditorial
Publié
Date de publication
11/2024
Peer-reviewed
Oui
Volume
43
Numéro
21
Pages
4922-4953
Langue
anglais
Notes
Publication types: Journal Article
Publication Status: ppublish
Publication Status: ppublish
Résumé
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.
Mots-clé
Mechanistic Target of Rapamycin Complex 1/metabolism, CD8-Positive T-Lymphocytes/immunology, CD8-Positive T-Lymphocytes/metabolism, Proto-Oncogene Proteins c-myc/metabolism, Proto-Oncogene Proteins c-myc/genetics, Signal Transduction, Animals, Interleukin-2/metabolism, Mice, Hydrogen-Ion Concentration, Mice, Inbred C57BL, Humans, Acidity, CD8+ T cell, IL-2, c-Myc, mTOR
Pubmed
Web of science
Open Access
Oui
Création de la notice
20/09/2024 13:20
Dernière modification de la notice
08/11/2024 18:56