PMID- 36076931 OWN - NLM STAT- MEDLINE DCOM- 20220912 LR - 20220930 IS - 1422-0067 (Electronic) IS - 1422-0067 (Linking) VI - 23 IP - 17 DP - 2022 Aug 23 TI - 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. LID - 10.3390/ijms23179534 [doi] LID - 9534 AB - 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 (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. FAU - Ara, Anjuman AU - Ara A AD - Cancer Research Cluster, Saskatchewan Cancer Agency, 20 Campus Drive, Saskatoon, SK S7N 4H4, Canada. AD - Division of Oncology, College of Medicine, University of Saskatchewan, 107 Wiggins Road, Saskatoon, SK S7N 5E5, Canada. FAU - Wu, Zhaojia AU - Wu Z AD - Cancer Research Cluster, Saskatchewan Cancer Agency, 20 Campus Drive, Saskatoon, SK S7N 4H4, Canada. AD - Division of Oncology, College of Medicine, University of Saskatchewan, 107 Wiggins Road, Saskatoon, SK S7N 5E5, Canada. FAU - Xu, Aizhang AU - Xu A AD - Cancer Research Cluster, Saskatchewan Cancer Agency, 20 Campus Drive, Saskatoon, SK S7N 4H4, Canada. AD - Division of Oncology, College of Medicine, University of Saskatchewan, 107 Wiggins Road, Saskatoon, SK S7N 5E5, Canada. FAU - Ahmed, Khawaja Ashfaque AU - Ahmed KA AD - Department of Pathology, Western College of Veterinary Medicine, University of Saskatchewan, Saskatoon, SK S7N 5B4, Canada. FAU - Leary, Scot C AU - Leary SC AD - Department of Biochemistry, Microbiology and Immunology, College of Medicine, University of Saskatchewan, 107 Wiggins Road, Saskatoon, SK S7N 5E5, Canada. FAU - Islam, Md Fahmid AU - Islam MF AD - Cancer Research Cluster, Saskatchewan Cancer Agency, 20 Campus Drive, Saskatoon, SK S7N 4H4, Canada. AD - Division of Oncology, College of Medicine, University of Saskatchewan, 107 Wiggins Road, Saskatoon, SK S7N 5E5, Canada. FAU - Chibbar, Rajni AU - Chibbar R AD - Department of Pathology, College of Medicine, University of Saskatchewan, 107 Wiggins Road, Saskatoon, SK S7N 5E5, Canada. FAU - Wu, Yue AU - Wu Y AD - Department of Pathology, College of Medicine, University of Saskatchewan, 107 Wiggins Road, Saskatoon, SK S7N 5E5, Canada. FAU - Xiang, Jim AU - Xiang J AD - Cancer Research Cluster, Saskatchewan Cancer Agency, 20 Campus Drive, Saskatoon, SK S7N 4H4, Canada. AD - Division of Oncology, College of Medicine, University of Saskatchewan, 107 Wiggins Road, Saskatoon, SK S7N 5E5, Canada. LA - eng GR - #PJT-153314/CAPMC/CIHR/Canada PT - Journal Article DEP - 20220823 PL - Switzerland TA - Int J Mol Sci JT - International journal of molecular sciences JID - 101092791 RN - 0 (Interleukin-15) RN - 0 (Interleukin-2) RN - EC 2.7.11.1 (Mechanistic Target of Rapamycin Complex 1) RN - EC 2.7.11.31 (AMP-Activated Protein Kinases) SB - IM MH - *AMP-Activated Protein Kinases/metabolism MH - Animals MH - *Autophagy/physiology MH - *Cell Differentiation MH - *Interleukin-15/pharmacology MH - *Interleukin-2 MH - Mammals MH - Mechanistic Target of Rapamycin Complex 1/metabolism MH - Mice MH - *Respiration MH - T-Lymphocytes PMC - PMC9455586 OTO - NOTNLM OT - AMPKalpha1 OT - FOXO1 OT - IL-15 OT - T-cell memory OT - autophagy OT - fatty acid oxidation OT - mTORC1 OT - mitochondrial biogenesis COIS- The authors declare no conflict of interest. EDAT- 2022/09/10 06:00 MHDA- 2022/09/14 06:00 PMCR- 2022/08/23 CRDT- 2022/09/09 01:05 PHST- 2022/06/23 00:00 [received] PHST- 2022/08/18 00:00 [revised] PHST- 2022/08/19 00:00 [accepted] PHST- 2022/09/09 01:05 [entrez] PHST- 2022/09/10 06:00 [pubmed] PHST- 2022/09/14 06:00 [medline] PHST- 2022/08/23 00:00 [pmc-release] AID - ijms23179534 [pii] AID - ijms-23-09534 [pii] AID - 10.3390/ijms23179534 [doi] PST - epublish SO - Int J Mol Sci. 2022 Aug 23;23(17):9534. doi: 10.3390/ijms23179534.