The Critical Role of AMPK alpha 1 in Regulating Autophagy and Mitochondrial Respiration in IL-15-Stimulated mTORC1(Weak) Signal-Induced T Cell Memory: An Interplay between Yin (AMPK alpha 1) and Yang (mTORC1) Energy Sensors in T Cell Differentiation

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 (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-alpha-1 (AMPK alpha 1), 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-1 alpha (PGC1 alpha), carnitine palmitoyl transferase-1 (CPT1 alpha), 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, AMPK alpha 1 deficiency abrogates these downstream responses to IL-15/mTORC1(Weak) signaling, leading to the upregulation of mTORC1 and hypoxia-inducible factor-1 alpha (HIF-1 alpha), 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 AMPK alpha 1-ULK1-ATG7 pathways, a finding that may greatly impact the development of efficient vaccines and immunotherapies for the treatment of cancer and infectious diseases.