| First Author | Ara A | Year | 2021 |
| Journal | Int J Mol Sci | Volume | 23 |
| Issue | 1 | PubMed ID | 35008461 |
| Mgi Jnum | J:331160 | Mgi Id | MGI:6853634 |
| Doi | 10.3390/ijms23010037 | Citation | Ara A, et al. (2021) The Energy Sensor AMPKalpha1 Is Critical in Rapamycin-Inhibition of mTORC1-S6K-Induced T-cell Memory. Int J Mol Sci 23(1) |
| abstractText | Energy sensors mTORC1 and AMPKalpha1 regulate T-cell metabolism and differentiation, while rapamycin (Rapa)-inhibition of mTORC1 (RIM) promotes T-cell memory. However, the underlying pathway and the role of AMPKalpha1 in Rapa-induced T-cell memory remain elusive. Using genetic and pharmaceutical tools, we demonstrate that Rapa promotes T-cell memory in mice in vivo post Listeria monocytogenesis rLmOVA infection and in vitro transition of effector T (TE) to memory T (TM) cells. IL-2- and IL-2+Rapa-stimulated T [IL-2/T and IL-2(Rapa+)/T] cells, when transferred into mice, differentiate into short-term IL-7R(-)CD62L(-)KLRG1(+) TE and long-lived IL-7R(+)CD62L(+)KLRG1(-) TM cells, respectively. To assess the underlying pathways, we performed Western blotting, confocal microscopy and Seahorse-assay analyses using IL-2/T and IL-2(Rapa+)/T-cells. We determined that IL-2(Rapa+)/T-cells activate transcription FOXO1, TCF1 and Eomes and metabolic pAMPKalpha1(T172), pULK1(S555) and ATG7 molecules and promote mitochondrial biogenesis and fatty-acid oxidation (FAO). We found that rapamycin-treated AMPKalpha-deficient AMPKalpha1-KO IL-2(Rapa+)/TM cells up-regulate transcription factor HIF-1alpha and induce a metabolic switch from FAO to glycolysis. Interestingly, despite the rapamycin treatment, AMPKalpha-deficient TM cells lost their cell survival capacity. Taken together, our data indicate that rapamycin promotes T-cell memory via transcriptional FOXO1-TCF1-Eomes programs and AMPKalpha1-ULK1-ATG7 metabolic axis, and that AMPKalpha1 plays a critical role in RIM-induced T-cell memory. |
