title: Foxp3 drives oxidative phosphorylation and protection from lipotoxicity.
abstract: Tregs can adopt a catabolic metabolic program with increased capacity for fatty acid oxidation-fueled oxidative phosphorylation (OXPHOS). It is unclear why this form of metabolism is favored in Tregs and, more specifically, whether this program represents an adaptation to the environment and developmental cues or is "hardwired" by Foxp3. Here we show, using metabolic analysis and an unbiased mass spectroscopy-based proteomics approach, that Foxp3 is both necessary and sufficient to program Treg-increased respiratory capacity and Tregs' increased ability to utilize fatty acids to fuel oxidative phosphorylation. Foxp3 drives upregulation of components of all the electron transport complexes, increasing their activity and ATP generation by oxidative phosphorylation. Increased fatty acid β-oxidation also results in selective protection of Foxp3+cells from fatty acid-induced cell death. This observation may provide novel targets for modulating Treg function or selection therapeutically.
authors.affiliation: Sir William Dunn School of Pathology.
authors.forename: Duncan
authors.initials: D
authors.lastname: Howie
authors.affiliation: Sir William Dunn School of Pathology.
authors.forename: Stephen Paul
authors.initials: SP
authors.lastname: Cobbold
authors.affiliation: Sir William Dunn School of Pathology.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Adams
authors.affiliation: Sir William Dunn School of Pathology.
authors.forename: Annemieke
authors.initials: A
authors.lastname: Ten Bokum
authors.affiliation: Sir William Dunn School of Pathology.
authors.forename: Andra Stefania
authors.initials: AS
authors.lastname: Necula
authors.affiliation: Nuffield Department of Obstetrics and Gynaecology, John Radcliffe Hospital.
authors.forename: Wei
authors.initials: W
authors.lastname: Zhang
authors.affiliation: Radcliffe Department of Medicine, John Radcliffe Hospital.
authors.forename: Honglei
authors.initials: H
authors.lastname: Huang
authors.affiliation: Radcliffe Department of Medicine, John Radcliffe Hospital.|National Health Service Blood and Transplant, John Radcliffe Hospital, University of Oxford, Oxford, England, United Kingdom.
authors.forename: David J
authors.initials: DJ
authors.lastname: Roberts
authors.affiliation: Sir William Dunn School of Pathology.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Thomas
authors.affiliation: Sir William Dunn School of Pathology.
authors.forename: Svenja S
authors.initials: SS
authors.lastname: Hester
authors.affiliation: Sir William Dunn School of Pathology.
authors.forename: David J
authors.initials: DJ
authors.lastname: Vaux
authors.affiliation: Sir William Dunn School of Pathology.
authors.forename: Alexander G
authors.initials: AG
authors.lastname: Betz
authors.affiliation: Sir William Dunn School of Pathology.
authors.forename: Herman
authors.initials: H
authors.lastname: Waldmann
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D002467:Cell Nucleus / Q000378:metabolism; D005227:Fatty Acids / Q000378:metabolism*; D005260:Female; D051858:Forkhead Transcription Factors / Q000378:metabolism*; D006801:Humans; D050356:Lipid Metabolism; D013058:Mass Spectrometry; D010085:Oxidative Phosphorylation; D040901:Proteomics / Q000379:methods*; D050378:T-Lymphocytes, Regulatory / Q000378:metabolism*; D015854:Up-Regulation
chemical_list: C418974:FOXP3 protein, human; D005227:Fatty Acids; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D000255:Adenosine Triphosphate