title: Manipulating the bioenergetics of alloreactive T cells causes their selective apoptosis and arrests graft-versus-host disease.
abstract: Cells generate adenosine triphosphate (ATP) by glycolysis and by oxidative phosphorylation (OXPHOS). Despite the importance of having sufficient ATP available for the energy-dependent processes involved in immune activation, little is known about the metabolic adaptations that occur in vivo to meet the increased demand for ATP in activated and proliferating lymphocytes. We found that bone marrow (BM) cells proliferating after BM transplantation (BMT) increased aerobic glycolysis but not OXPHOS, whereas T cells proliferating in response to alloantigens during graft-versus-host disease (GVHD) increased both aerobic glycolysis and OXPHOS. Metabolomic analysis of alloreactive T cells showed an accumulation of acylcarnitines consistent with changes in fatty acid oxidation. Alloreactive T cells also exhibited a hyperpolarized mitochondrial membrane potential (ΔΨm), increased superoxide production, and decreased amounts of antioxidants, whereas proliferating BM cells did not. Bz-423, a small-molecule inhibitor of the mitochondrial F(1)F(0) adenosine triphosphate synthase (F(1)F(0)-ATPase), selectively increased superoxide and induced the apoptosis of alloreactive T cells, which arrested established GVHD in several BMT models without affecting hematopoietic engraftment or lymphocyte reconstitution. These findings challenge the current paradigm that activated T cells meet their increased demands for ATP through aerobic glycolysis, and identify the possibility that bioenergetic and redox characteristics can be selectively exploited as a therapeutic strategy for immune disorders.
authors.affiliation: Department of Pediatrics, University of Michigan, Ann Arbor, MI 48109, USA.
authors.forename: Erin
authors.initials: E
authors.lastname: Gatza
authors.forename: Daniel R
authors.initials: DR
authors.lastname: Wahl
authors.forename: Anthony W
authors.initials: AW
authors.lastname: Opipari
authors.forename: Thomas B
authors.initials: TB
authors.lastname: Sundberg
authors.forename: Pavan
authors.initials: P
authors.lastname: Reddy
authors.forename: Chen
authors.initials: C
authors.lastname: Liu
authors.forename: Gary D
authors.initials: GD
authors.lastname: Glick
authors.forename: James L M
authors.initials: JL
authors.lastname: Ferrara
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000276:immunology*; D001569:Benzodiazepines / Q000494:pharmacology / Q000627:therapeutic use; D001854:Bone Marrow Cells / Q000378:metabolism; D016026:Bone Marrow Transplantation / Q000276:immunology; D005260:Female; D006086:Graft vs Host Disease / Q000188:drug therapy / Q000276:immunology*; D007519:Isoantigens / Q000276:immunology*; D007773:Lactates / Q000378:metabolism; D008213:Lymphocyte Activation; D055442:Metabolome; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D025261:Mitochondrial Proton-Translocating ATPases / Q000037:antagonists & inhibitors / Q000378:metabolism; D010085:Oxidative Phosphorylation; D010101:Oxygen Consumption; D017382:Reactive Oxygen Species / Q000378:metabolism; D013601:T-Lymphocytes / Q000187:drug effects / Q000378:metabolism*
chemical_list: D007519:Isoantigens; D007773:Lactates; D017382:Reactive Oxygen Species; D001569:Benzodiazepines; C474451:F1F0-ATP synthase; D025261:Mitochondrial Proton-Translocating ATPases; C468549:Bz-423