Resveratrol stimulates the metabolic reprogramming of human CD4+ T cells to enhance effector function.
Marco CraveiroGaspard CretenetCédric MongellazMaria I MatiasOlivier CaronMaria C Pedroso de LimaValérie S ZimmermannEric SolaryValérie DardalhonVjekoslav DulićNaomi TaylorPublished in: Science signaling (2017)
The polyphenol resveratrol activates the deacetylase Sirt1, resulting in various antioxidant, chemoprotectant, neuroprotective, cardioprotective, and anti-inflammatory properties. We found that at high concentrations of resveratrol, human CD4+ T cells showed defective antigen receptor signaling and arrest at the G1 stage of the cell cycle, whereas at low concentrations, cells were readily activated and exhibited enhanced Sirt1 deacetylase activity. Nevertheless, low-dose resveratrol rapidly stimulated genotoxic stress in the T cells, which resulted in engagement of a DNA damage response pathway that depended on the kinase ATR [ataxia telangiectasia-mutated (ATM) and Rad3-related], but not ATM, and subsequently in premitotic cell cycle arrest. The concomitant activation of p53 was coupled to the expression of gene products that regulate cell metabolism, leading to a metabolic reprogramming that was characterized by decreased glycolysis, increased glutamine consumption, and a shift to oxidative phosphorylation. These alterations in the bioenergetic homeostasis of CD4+ T cells resulted in enhanced effector function, with both naïve and memory CD4+ T cells secreting increased amounts of the inflammatory cytokine interferon-γ. Thus, our data highlight the wide range of metabolic adaptations that CD4+ T lymphocytes undergo in response to genomic stress.
Keyphrases
- dna damage response
- cell cycle
- cell cycle arrest
- dna repair
- oxidative stress
- endothelial cells
- anti inflammatory
- low dose
- dna damage
- cell death
- dendritic cells
- pi k akt
- cell proliferation
- induced apoptosis
- copy number
- induced pluripotent stem cells
- poor prognosis
- regulatory t cells
- pluripotent stem cells
- ischemia reperfusion injury
- protein kinase
- single cell
- stem cells
- working memory
- stress induced
- early onset
- genome wide
- type iii
- tyrosine kinase
- cell therapy
- binding protein
- subarachnoid hemorrhage
- electronic health record
- high intensity
- big data
- brain injury
- long non coding rna
- drug induced
- deep learning