The Critical Role of AMPKα1 in Regulating Autophagy and Mitochondrial Respiration in IL-15-Stimulated mTORC1(Weak) Signal-Induced T Cell Memory: An Interplay between Yin (AMPKα1) and Yang (mTORC1) Energy Sensors in T Cell Differentiation

Two common γ-chain family cytokines IL-2 and IL-15 stimulate the same mammalian target of rapamycin complex-1 (mTORC1) signaling yet induce effector T (T(E)) and memory T (T(M)) cell differentiation via a poorly understood mechanism(s). Here, we prepared in vitro IL-2-stimulated T(E) (IL-2/T(E)) and IL-15-stimulated T(M) (IL-15/T(M)) 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/T(E) and CD62L(+)KLRG(−) IL-15/T(M) 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-α-1 (AMPKα1), 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-γ coactivator-1α (PGC1α), carnitine palmitoyl transferase-1 (CPT1α), 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, AMPKα1 deficiency abrogates these downstream responses to IL-15/mTORC1(Weak) signaling, leading to the upregulation of mTORC1 and hypoxia-inducible factor-1α (HIF-1α), 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 AMPKα1-ULK1-ATG7 pathways, a finding that may greatly impact the development of efficient vaccines and immunotherapies for the treatment of cancer and infectious diseases.