The Energy Sensor AMPKα1 Is Critical in Rapamycin-Inhibition of mTORC1-S6K-Induced T-cell Memory.
Anjuman AraAizhang XuKhawaja Ashfaque AhmedScot C LearyMd Fahmid IslamZhaojia WuRajni ChibbarJim XiangPublished in: International journal of molecular sciences (2021)
Energy sensors mTORC1 and AMPKα1 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 AMPKα1 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 (T E ) to memory T (T M ) 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 + T E and long-lived IL-7R + CD62L + KLRG1 - T M 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 pAMPKα1(T 172 ), pULK1(S 555 ) and ATG7 molecules and promote mitochondrial biogenesis and fatty-acid oxidation (FAO). We found that rapamycin-treated AMPKα-deficient AMPKα1-KO IL-2(Rapa+)/T M cells up-regulate transcription factor HIF-1α and induce a metabolic switch from FAO to glycolysis. Interestingly, despite the rapamycin treatment, AMPKα-deficient T M cells lost their cell survival capacity. Taken together, our data indicate that rapamycin promotes T-cell memory via transcriptional FOXO1-TCF1-Eomes programs and AMPKα1-ULK1-ATG7 metabolic axis, and that AMPKα1 plays a critical role in RIM-induced T-cell memory.
Keyphrases
- transcription factor
- induced apoptosis
- skeletal muscle
- working memory
- cell cycle arrest
- fatty acid
- signaling pathway
- protein kinase
- high glucose
- oxidative stress
- public health
- metabolic syndrome
- diabetic rats
- endothelial cells
- gene expression
- endoplasmic reticulum stress
- genome wide analysis
- nitric oxide
- insulin resistance
- drug induced
- immune response
- south africa
- artificial intelligence
- low cost
- heat shock
- newly diagnosed
- dna methylation