Glycolysis promotes caspase-3 activation in lipid rafts in T cells

• Published in: Cell death & disease 2018-01, Vol.9 (2), p.62-13, Article 62
• Main Authors: Secinaro, Michael A., Fortner, Karen A., Dienz, Oliver, Logan, Angela, Murphy, Michael P., Anathy, Vikas, Boyson, Jonathan E., Budd, Ralph C.
• Format: Article
• Language: English
• Subjects: Antibodies; Apoptosis; Biochemistry; Biomedical and Life Sciences; Caspase; Caspase 3 - metabolism; Caspase-3; Caspase-7; Caspase-8; Caspase-9; Cell activation; Cell Biology; Cell Culture; Cell death; Deoxyglucose; Effector cells; Electron transport; Glycolysis; Glycolysis - genetics; Humans; Immunology; Influenza; Interleukin 15; Interleukin 2; Life Sciences; Lipid rafts; Lymphocytes; Lymphocytes T; Metabolism; Mitochondria; Mitochondrial DNA; Oxidative phosphorylation; Phosphorylation; T-Lymphocytes - metabolism
• ISSN: 2041-4889; 2041-4889
• DOI: 10.1038/s41419-017-0099-z

Resting T cells undergo a rapid metabolic shift to glycolysis upon activation in the presence of interleukin (IL)-2, in contrast to oxidative mitochondrial respiration with IL-15. Paralleling these different metabolic states are striking differences in susceptibility to restimulation-induced cell death (RICD); glycolytic effector T cells are highly sensitive to RICD, whereas non-glycolytic T cells are resistant. It is unclear whether the metabolic state of a T cell is linked to its susceptibility to RICD. Our findings reveal that IL-2-driven glycolysis promotes caspase-3 activity and increases sensitivity to RICD. Neither caspase-7, caspase-8, nor caspase-9 activity is affected by these metabolic differences. Inhibition of glycolysis with 2-deoxyglucose reduces caspase-3 activity as well as sensitivity to RICD. By contrast, IL-15-driven oxidative phosphorylation actively inhibits caspase-3 activity through its glutathionylation. We further observe active caspase-3 in the lipid rafts of glycolytic but not non-glycolytic T cells, suggesting a proximity-induced model of self-activation. Finally, we observe that effector T cells during influenza infection manifest higher levels of active caspase-3 than naive T cells. Collectively, our findings demonstrate that glycolysis drives caspase-3 activity and susceptibility to cell death in effector T cells independently of upstream caspases. Linking metabolism, caspase-3 activity, and cell death provides an intrinsic mechanism for T cells to limit the duration of effector function.