| First Author | Ara A | Year | 2022 |
| Journal | Int J Mol Sci | Volume | 23 |
| Issue | 17 | PubMed ID | 36076931 |
| Mgi Jnum | J:354840 | Mgi Id | MGI:7340627 |
| Doi | 10.3390/ijms23179534 | Citation | Ara A, et al. (2022) The Critical Role of AMPKalpha1 in Regulating Autophagy and Mitochondrial Respiration in IL-15-Stimulated mTORC1(Weak) Signal-Induced T Cell Memory: An Interplay between Yin (AMPKalpha1) and Yang (mTORC1) Energy Sensors in T Cell Differentiation. Int J Mol Sci 23(17) |
| abstractText | Two common gamma-chain family cytokines IL-2 and IL-15 stimulate the same mammalian target of rapamycin complex-1 (mTORC1) signaling yet induce effector T (TE) and memory T (TM) cell differentiation via a poorly understood mechanism(s). Here, we prepared in vitro IL-2-stimulated TE (IL-2/TE) and IL-15-stimulated TM (IL-15/TM) cells for characterization by flow cytometry, Western blotting, confocal microscopy and Seahorse-assay analyses. We demonstrate that IL-2 and IL-15 stimulate strong and weak mTORC1 signals, respectively, which lead to the formation of CD62 ligand (CD62L)(-) killer cell lectin-like receptor subfamily G member-1 (KLRG)(+) IL-2/TE and CD62L(+)KLRG(-) IL-15/TM cells with short- and long-term survival following their adoptive transfer into mice. The IL-15/mTORC1(Weak) signal activates the forkhead box-O-1 (FOXO1), T cell factor-1 (TCF1) and Eomes transcriptional network and the metabolic adenosine monophosphate-activated protein kinase-alpha-1 (AMPKalpha1), Unc-51-like autophagy-activating kinase-1 (ULK1) and autophagy-related gene-7 (ATG7) axis, increasing the expression of mitochondrial regulators aquaporin-9 (AQP9), mitochondrial transcription factor-A (TFAM), peroxisome proliferator-activated receptor-gamma coactivator-1alpha (PGC1alpha), carnitine palmitoyl transferase-1 (CPT1alpha), microtubule-associated protein light chain-3 II (LC3II), Complex I and ortic atrophy-1 (OPA1), leading to promoting mitochondrial biogenesis and fatty-acid oxidation (FAO). Interestingly, AMPKalpha1 deficiency abrogates these downstream responses to IL-15/mTORC1(Weak) signaling, leading to the upregulation of mTORC1 and hypoxia-inducible factor-1alpha (HIF-1alpha), a metabolic switch from FAO to glycolysis and reduced cell survival. Taken together, our data demonstrate that IL-15/mTORC1(Weak) signaling controls T-cell memory via activation of the transcriptional FOXO1-TCF1-Eomes and metabolic AMPKalpha1-ULK1-ATG7 pathways, a finding that may greatly impact the development of efficient vaccines and immunotherapies for the treatment of cancer and infectious diseases. |
