title: Sensitivity to Restimulation-Induced Cell Death Is Linked to Glycolytic Metabolism in Human T Cells.
abstract: Restimulation-induced cell death (RICD) regulates immune responses by restraining effector T cell expansion and limiting nonspecific damage to the host. RICD is triggered by re-engagement of the TCR on a cycling effector T cell, resulting in apoptosis. It remains unclear how RICD sensitivity is calibrated in T cells derived from different individuals or subsets. In this study we show that aerobic glycolysis strongly correlates with RICD sensitivity in human CD8+effector T cells. Reducing glycolytic activity or glucose availability rendered effector T cells significantly less sensitive to RICD. We found that active glycolysis specifically facilitates the induction of proapoptotic Fas ligand upon TCR restimulation, accounting for enhanced RICD sensitivity in highly glycolytic T cells. Collectively, these data indicate that RICD susceptibility is linked to metabolic reprogramming, and that switching back to metabolic quiescence may help shield T cells from RICD as they transition into the memory pool.
authors.affiliation: Department of Pharmacology and Molecular Therapeutics, Uniformed Services University of the Health Sciences, Bethesda, MD 20814; and.
authors.forename: Sasha E
authors.initials: SE
authors.lastname: Larsen
authors.affiliation: Department of Pharmacology and Molecular Therapeutics, Uniformed Services University of the Health Sciences, Bethesda, MD 20814; and.
authors.forename: Abegail
authors.initials: A
authors.lastname: Bilenkin
authors.affiliation: Metabolism, Infection and Immunity Unit, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892.
authors.forename: Tatiana N
authors.identifier: 0000-0002-6560-0985
authors.initials: TN
authors.lastname: Tarasenko
authors.affiliation: Department of Pharmacology and Molecular Therapeutics, Uniformed Services University of the Health Sciences, Bethesda, MD 20814; and.
authors.forename: Swadhinya
authors.initials: S
authors.lastname: Arjunaraja
authors.affiliation: Department of Pharmacology and Molecular Therapeutics, Uniformed Services University of the Health Sciences, Bethesda, MD 20814; and.
authors.forename: Jeffrey R
authors.identifier: 0000-0002-4157-3185
authors.initials: JR
authors.lastname: Stinson
authors.affiliation: Metabolism, Infection and Immunity Unit, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892.
authors.forename: Peter J
authors.identifier: 0000-0001-5601-3044
authors.initials: PJ
authors.lastname: McGuire
authors.affiliation: Department of Pharmacology and Molecular Therapeutics, Uniformed Services University of the Health Sciences, Bethesda, MD 20814; and andrew.snow@usuhs.edu.
authors.forename: Andrew L
authors.identifier: 0000-0002-8728-6691
authors.initials: AL
authors.lastname: Snow
mesh_terms: D017209:Apoptosis / Q000276:immunology*; D015153:Blotting, Western; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism*; D002478:Cells, Cultured; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D006019:Glycolysis / Q000276:immunology*; D006801:Humans; D060888:Real-Time Polymerase Chain Reaction