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- W4313404881 abstract "Abstract Energy sensors mTORC1 and AMPKα1 regulate T-cell metabolism and differentiation, while rapamycin (Rapa), an inhibitor of mTORC1, supports T-cell memory. However, the underlying pathway, the exact mechanisms, and the role of AMPKα1 in Rapa-induced T-cell memory is not well understood. Using the Listeria monocytogenes (rLmOVA) infection model and genetic and pharmaceutical tools, we demonstrate that Rapa promotes T-cell memory in mice post-rLmOVA infection. When T-cells stimulated in vitro in the presence of IL-2 without rapamycin (IL-2/T) or with rapamycin (IL-2+Rapa /T) and transferred into mice, it differentiated into short-term effector T (TE) [IL-7R−CD62L−KLRG1+] and long-lived memory T (TM) [IL-7R+CD62L+KLRG1−] cells, respectively. We determined that rapamycin-treated T cells activated transcriptional factors, FOXO1, TCF1 and Eomes and metabolic pAMPKα1(T172), pULK1(S555), and ATG7 molecules and promoted mitochondrial biogenesis and oxidative phosphorylation (OXPHOS). Using Seahorse-real time metabolic analyzer, we found that rapamycin-treated AMPKα-deficient TM cells up-regulated transcription factor HIF-1α and induced a metabolic switch from OXPHOS to glycolysis. Interestingly, despite the rapamycin treatment, AMPKα-deficient TM cells lost their cell survival capacity. Altogether, our data provide a mechanistic explanation for enhanced T-cell survival after rapamycin treatment and suggest that rapamycin promotes T-cell memory via transcriptional FOXO1-TCF1-Eomes programs and AMPKα1-ULK1-ATG7 metabolic axis. And AMPKα1 plays a critical role in rapamycin-induced increased survival and metabolic switching of CTLs during the transition of effector to memory T cells. Supported by Canadian Institutes of Health Research grant (409228). Saskatchewan Health Research Foundation (SHRF) postdoctoral fellowship." @default.
- W4313404881 created "2023-01-06" @default.
- W4313404881 creator A5071965865 @default.
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- W4313404881 date "2022-05-01" @default.
- W4313404881 modified "2023-10-16" @default.
- W4313404881 title "A critical role of energy sensor AMPKα1 in rapamycin dependent memory CD8+ T cell survival" @default.
- W4313404881 doi "https://doi.org/10.4049/jimmunol.208.supp.55.08" @default.
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