title: Programmed death-1 controls T cell survival by regulating oxidative metabolism.
abstract: The coinhibitory receptor programmed death-1 (PD-1) maintains immune homeostasis by negatively regulating T cell function and survival. Blockade of PD-1 increases the severity of graft-versus-host disease (GVHD), but the interplay between PD-1 inhibition and T cell metabolism is not well studied. We found that both murine and human alloreactive T cells concomitantly upregulated PD-1 expression and increased levels of reactive oxygen species (ROS) following allogeneic bone marrow transplantation. This PD-1(Hi)ROS(Hi) phenotype was specific to alloreactive T cells and was not observed in syngeneic T cells during homeostatic proliferation. Blockade of PD-1 signaling decreased both mitochondrial H2O2 and total cellular ROS levels, and PD-1-driven increases in ROS were dependent upon the oxidation of fatty acids, because treatment with etomoxir nullified changes in ROS levels following PD-1 blockade. Downstream of PD-1, elevated ROS levels impaired T cell survival in a process reversed by antioxidants. Furthermore, PD-1-driven changes in ROS were fundamental to establishing a cell's susceptibility to subsequent metabolic inhibition, because blockade of PD-1 decreased the efficacy of later F1F0-ATP synthase modulation. These data indicate that PD-1 facilitates apoptosis in alloreactive T cells by increasing ROS in a process dependent upon the oxidation of fat. In addition, blockade of PD-1 undermines the potential for subsequent metabolic inhibition, an important consideration given the increasing use of anti-PD-1 therapies in the clinic.
authors.affiliation: Department of Pediatrics, University of Michigan, Ann Arbor, MI 48109;
authors.forename: Victor
authors.initials: V
authors.lastname: Tkachev
authors.affiliation: Department of Pediatrics, University of Michigan, Ann Arbor, MI 48109;
authors.forename: Stefanie
authors.initials: S
authors.lastname: Goodell
authors.affiliation: Department of Obstetrics and Gynecology, University of Michigan, Ann Arbor, MI 48109;
authors.forename: Anthony W
authors.initials: AW
authors.lastname: Opipari
authors.affiliation: Lycera Corporation, Ann Arbor, MI 48109;
authors.forename: Ling-Yang
authors.initials: LY
authors.lastname: Hao
authors.affiliation: Lycera Corporation, Ann Arbor, MI 48109;
authors.forename: Luigi
authors.initials: L
authors.lastname: Franchi
authors.affiliation: Department of Chemistry, University of Michigan, Ann Arbor, MI 48109; and.
authors.forename: Gary D
authors.initials: GD
authors.lastname: Glick
authors.affiliation: Department of Pediatrics, University of Michigan, Ann Arbor, MI 48109;
authors.forename: James L M
authors.initials: JL
authors.lastname: Ferrara
authors.affiliation: Division of Blood and Marrow Transplant and Cellular Therapies, Department of Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, PA 15224 craig.byersdorfer@chp.edu.
authors.forename: Craig A
authors.initials: CA
authors.lastname: Byersdorfer
mesh_terms: D000818:Animals; D000941:Antigens / Q000276:immunology; D017209:Apoptosis / Q000235:genetics / Q000276:immunology; D016026:Bone Marrow Transplantation / Q000009:adverse effects; D002470:Cell Survival / Q000235:genetics; D005227:Fatty Acids / Q000378:metabolism; D005260:Female; D015870:Gene Expression; D006086:Graft vs Host Disease / Q000209:etiology; D064593:Heterografts; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D010084:Oxidation-Reduction; D010641:Phenotype; D061026:Programmed Cell Death 1 Receptor / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism*
chemical_list: D000941:Antigens; D005227:Fatty Acids; D061026:Programmed Cell Death 1 Receptor; D017382:Reactive Oxygen Species