title: Effector T cells require fatty acid metabolism during murine graft-versus-host disease.
abstract: Activated T cells require increased energy to proliferate and mediate effector functions, but the metabolic changes that occur in T cells following stimulation in vivo are poorly understood, particularly in the context of inflammation. We have previously shown that T cells activated during graft-versus-host disease (GVHD) primarily rely on oxidative phosphorylation to synthesize adenosine 5'-triphosphate. Here, we demonstrate that alloreactive effector T cells (Teff) use fatty acids (FAs) as a fuel source to support their in vivo activation. Alloreactive T cells increased FA transport, elevated levels of FA oxidation enzymes, up-regulated transcriptional coactivators to drive oxidative metabolism, and increased their rates of FA oxidation. Importantly, increases in FA transport and up-regulation of FA oxidation machinery occurred specifically in T cells during GVHD and were not seen in Teff following acute activation. Pharmacological blockade of FA oxidation decreased the survival of alloreactive T cells but did not influence the survival of T cells during normal immune reconstitution. These studies suggest that pathways controlling FA metabolism might serve as therapeutic targets to treat GVHD and other T-cell-mediated immune diseases.
authors.affiliation: Department of Pediatrics.
authors.forename: Craig A
authors.initials: CA
authors.lastname: Byersdorfer
authors.forename: Victor
authors.initials: V
authors.lastname: Tkachev
authors.forename: Anthony W
authors.initials: AW
authors.lastname: Opipari
authors.forename: Stefanie
authors.initials: S
authors.lastname: Goodell
authors.forename: Jacob
authors.initials: J
authors.lastname: Swanson
authors.forename: Stacy
authors.initials: S
authors.lastname: Sandquist
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; D015153:Blotting, Western; D016026:Bone Marrow Transplantation / Q000379:methods; D002334:Carnitine O-Palmitoyltransferase / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004852:Epoxy Compounds / Q000494:pharmacology; D005227:Fatty Acids / Q000276:immunology* / Q000378:metabolism; D005260:Female; D005434:Flow Cytometry; D006086:Graft vs Host Disease / Q000276:immunology* / Q000378:metabolism; D008213:Lymphocyte Activation / Q000276:immunology*; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D010084:Oxidation-Reduction; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016176:T-Lymphocyte Subsets / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D014157:Transcription Factors / Q000276:immunology / Q000378:metabolism; D014184:Transplantation, Homologous
chemical_list: D004791:Enzyme Inhibitors; D004852:Epoxy Compounds; D005227:Fatty Acids; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C485290:Ppargc1a protein, mouse; D014157:Transcription Factors; D002334:Carnitine O-Palmitoyltransferase; C054207:etomoxir
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