Resveratrol stimulates the metabolic reprogramming of human CD4+ T cells to enhance effector function

Marco Craveiro1,2,*, Gaspard Cretenet1,*, Cédric Mongellaz1, Maria I. Matias1, Olivier Caron3,4, Maria C. Pedroso de Lima2, Valérie S. Zimmermann1, Eric Solary3,4, Valérie Dardalhon1, Vjekoslav Dulić1,†, and Naomi Taylor1,† 1IGMM, CNRS, Université de Montpellier, Montpellier, France. 2CNC–Centre for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal. 3INSERM U1170, Gustave Roussy Cancer Center, Villejuif, France. 4Faculty of Medicine, Université Paris-Sud, Le Kremlin-Bicêtre, France. ↵†Corresponding author. Email: vjekoslav.dulic@igmm.cnrs.fr (V.D.); taylor@igmm.cnrs.fr (N.T.) ↵* These authors contributed equally to this work. Hide authors and affiliations Sci. Signal. 17 Oct 2017: Vol. 10, Issue 501, eaal3024 DOI: 10.1126/scisignal.aal3024 Article Figures & Data Resveratrol and lymphocyte responses Resveratrol is a polyphenolic plant compound, which has attracted much interest as a pharmacological agent because of its potential therapeutic effects against cancer, aging, and inflammation. However, many studies have produced conflicting evidence of the effects of resveratrol in different contexts. Craveiro et al. found that high doses of resveratrol inhibited the responses of human CD4+ T cells to antigens. However, low doses of the drug reprogrammed the metabolism of the cells to make them more responsive to antigens and produce increased amounts of the inflammatory cytokine interferon-γ. These data suggest that the use of resveratrol to treat various pathologies should be carefully assessed, especially in an autoimmune setting. Abstract 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. http://www.sciencemag.org/about/science-licenses-journal-article-reuse