title: Essential role of mitochondrial energy metabolism in Foxp3⁺ T-regulatory cell function and allograft survival.
abstract: Conventional T (Tcon) cells and Foxp3(+) T-regulatory (Treg) cells are thought to have differing metabolic requirements, but little is known of mitochondrial functions within these cell populations in vivo. In murine studies, we found that activation of both Tcon and Treg cells led to myocyte enhancer factor 2 (Mef2)-induced expression of genes important to oxidative phosphorylation (OXPHOS). Inhibition of OXPHOS impaired both Tcon and Treg cell function compared to wild-type cells but disproportionally affected Treg cells. Deletion of Pgc1α or Sirt3, which are key regulators of OXPHOS, abrogated Treg-dependent suppressive function and impaired allograft survival. Mef2 is inhibited by histone/protein deacetylase-9 (Hdac9), and Hdac9 deletion increased Treg suppressive function. Hdac9(-/-) Treg showed increased expression of Pgc1α and Sirt3, and improved mitochondrial respiration, compared to wild-type Treg cells. Our data show that key OXPHOS regulators are required for optimal Treg function and Treg-dependent allograft acceptance. These findings provide a novel approach to increase Treg function and give insights into the fundamental mechanisms by which mitochondrial energy metabolism regulates immune cell functions in vivo.
authors: *Department of Pediatrics, Division of Nephrology, Center for Mitochondrial and Epigenomic Medicine, and Department of Pathology and Laboratory Medicine, Division of Transplant Immunology, and Biesecker Center for Pediatric Liver Disease, Children's Hospital of Philadelphia and University of Pennsylvania; Department of Medicine, Center for Sleep and Circadian Neurobiology, and Department of Physiology and Institute of Diabetes, Obesity, and Metabolism, University of Pennsylvania; and Division of Traumatology and Surgical Critical Care, Hospital of the University of Pennsylvania, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
authors: Ulf H
authors: UH
authors: Beier
authors: *Department of Pediatrics, Division of Nephrology, Center for Mitochondrial and Epigenomic Medicine, and Department of Pathology and Laboratory Medicine, Division of Transplant Immunology, and Biesecker Center for Pediatric Liver Disease, Children's Hospital of Philadelphia and University of Pennsylvania; Department of Medicine, Center for Sleep and Circadian Neurobiology, and Department of Physiology and Institute of Diabetes, Obesity, and Metabolism, University of Pennsylvania; and Division of Traumatology and Surgical Critical Care, Hospital of the University of Pennsylvania, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
authors: Alessia
authors: A
authors: Angelin
authors: *Department of Pediatrics, Division of Nephrology, Center for Mitochondrial and Epigenomic Medicine, and Department of Pathology and Laboratory Medicine, Division of Transplant Immunology, and Biesecker Center for Pediatric Liver Disease, Children's Hospital of Philadelphia and University of Pennsylvania; Department of Medicine, Center for Sleep and Circadian Neurobiology, and Department of Physiology and Institute of Diabetes, Obesity, and Metabolism, University of Pennsylvania; and Division of Traumatology and Surgical Critical Care, Hospital of the University of Pennsylvania, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
authors: Tatiana
authors: T
authors: Akimova
authors: *Department of Pediatrics, Division of Nephrology, Center for Mitochondrial and Epigenomic Medicine, and Department of Pathology and Laboratory Medicine, Division of Transplant Immunology, and Biesecker Center for Pediatric Liver Disease, Children's Hospital of Philadelphia and University of Pennsylvania; Department of Medicine, Center for Sleep and Circadian Neurobiology, and Department of Physiology and Institute of Diabetes, Obesity, and Metabolism, University of Pennsylvania; and Division of Traumatology and Surgical Critical Care, Hospital of the University of Pennsylvania, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
authors: Liqing
authors: L
authors: Wang
authors: *Department of Pediatrics, Division of Nephrology, Center for Mitochondrial and Epigenomic Medicine, and Department of Pathology and Laboratory Medicine, Division of Transplant Immunology, and Biesecker Center for Pediatric Liver Disease, Children's Hospital of Philadelphia and University of Pennsylvania; Department of Medicine, Center for Sleep and Circadian Neurobiology, and Department of Physiology and Institute of Diabetes, Obesity, and Metabolism, University of Pennsylvania; and Division of Traumatology and Surgical Critical Care, Hospital of the University of Pennsylvania, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
authors: Yujie
authors: Y
authors: Liu
authors: *Department of Pediatrics, Division of Nephrology, Center for Mitochondrial and Epigenomic Medicine, and Department of Pathology and Laboratory Medicine, Division of Transplant Immunology, and Biesecker Center for Pediatric Liver Disease, Children's Hospital of Philadelphia and University of Pennsylvania; Department of Medicine, Center for Sleep and Circadian Neurobiology, and Department of Physiology and Institute of Diabetes, Obesity, and Metabolism, University of Pennsylvania; and Division of Traumatology and Surgical Critical Care, Hospital of the University of Pennsylvania, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
authors: Haiyan
authors: H
authors: Xiao
authors: *Department of Pediatrics, Division of Nephrology, Center for Mitochondrial and Epigenomic Medicine, and Department of Pathology and Laboratory Medicine, Division of Transplant Immunology, and Biesecker Center for Pediatric Liver Disease, Children's Hospital of Philadelphia and University of Pennsylvania; Department of Medicine, Center for Sleep and Circadian Neurobiology, and Department of Physiology and Institute of Diabetes, Obesity, and Metabolism, University of Pennsylvania; and Division of Traumatology and Surgical Critical Care, Hospital of the University of Pennsylvania, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
authors: Maya A
authors: MA
authors: Koike
authors: *Department of Pediatrics, Division of Nephrology, Center for Mitochondrial and Epigenomic Medicine, and Department of Pathology and Laboratory Medicine, Division of Transplant Immunology, and Biesecker Center for Pediatric Liver Disease, Children's Hospital of Philadelphia and University of Pennsylvania; Department of Medicine, Center for Sleep and Circadian Neurobiology, and Department of Physiology and Institute of Diabetes, Obesity, and Metabolism, University of Pennsylvania; and Division of Traumatology and Surgical Critical Care, Hospital of the University of Pennsylvania, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
authors: Saege A
authors: SA
authors: Hancock
authors: *Department of Pediatrics, Division of Nephrology, Center for Mitochondrial and Epigenomic Medicine, and Department of Pathology and Laboratory Medicine, Division of Transplant Immunology, and Biesecker Center for Pediatric Liver Disease, Children's Hospital of Philadelphia and University of Pennsylvania; Department of Medicine, Center for Sleep and Circadian Neurobiology, and Department of Physiology and Institute of Diabetes, Obesity, and Metabolism, University of Pennsylvania; and Division of Traumatology and Surgical Critical Care, Hospital of the University of Pennsylvania, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
authors: Tricia R
authors: TR
authors: Bhatti
authors: *Department of Pediatrics, Division of Nephrology, Center for Mitochondrial and Epigenomic Medicine, and Department of Pathology and Laboratory Medicine, Division of Transplant Immunology, and Biesecker Center for Pediatric Liver Disease, Children's Hospital of Philadelphia and University of Pennsylvania; Department of Medicine, Center for Sleep and Circadian Neurobiology, and Department of Physiology and Institute of Diabetes, Obesity, and Metabolism, University of Pennsylvania; and Division of Traumatology and Surgical Critical Care, Hospital of the University of Pennsylvania, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
authors: Rongxiang
authors: R
authors: Han
authors: *Department of Pediatrics, Division of Nephrology, Center for Mitochondrial and Epigenomic Medicine, and Department of Pathology and Laboratory Medicine, Division of Transplant Immunology, and Biesecker Center for Pediatric Liver Disease, Children's Hospital of Philadelphia and University of Pennsylvania; Department of Medicine, Center for Sleep and Circadian Neurobiology, and Department of Physiology and Institute of Diabetes, Obesity, and Metabolism, University of Pennsylvania; and Division of Traumatology and Surgical Critical Care, Hospital of the University of Pennsylvania, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
authors: Jing
authors: J
authors: Jiao
authors: *Department of Pediatrics, Division of Nephrology, Center for Mitochondrial and Epigenomic Medicine, and Department of Pathology and Laboratory Medicine, Division of Transplant Immunology, and Biesecker Center for Pediatric Liver Disease, Children's Hospital of Philadelphia and University of Pennsylvania; Department of Medicine, Center for Sleep and Circadian Neurobiology, and Department of Physiology and Institute of Diabetes, Obesity, and Metabolism, University of Pennsylvania; and Division of Traumatology and Surgical Critical Care, Hospital of the University of Pennsylvania, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
authors: Sigrid C
authors: SC
authors: Veasey
authors: *Department of Pediatrics, Division of Nephrology, Center for Mitochondrial and Epigenomic Medicine, and Department of Pathology and Laboratory Medicine, Division of Transplant Immunology, and Biesecker Center for Pediatric Liver Disease, Children's Hospital of Philadelphia and University of Pennsylvania; Department of Medicine, Center for Sleep and Circadian Neurobiology, and Department of Physiology and Institute of Diabetes, Obesity, and Metabolism, University of Pennsylvania; and Division of Traumatology and Surgical Critical Care, Hospital of the University of Pennsylvania, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
authors: Carrie A
authors: CA
authors: Sims
authors: *Department of Pediatrics, Division of Nephrology, Center for Mitochondrial and Epigenomic Medicine, and Department of Pathology and Laboratory Medicine, Division of Transplant Immunology, and Biesecker Center for Pediatric Liver Disease, Children's Hospital of Philadelphia and University of Pennsylvania; Department of Medicine, Center for Sleep and Circadian Neurobiology, and Department of Physiology and Institute of Diabetes, Obesity, and Metabolism, University of Pennsylvania; and Division of Traumatology and Surgical Critical Care, Hospital of the University of Pennsylvania, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
authors: Joseph A
authors: JA
authors: Baur
authors: *Department of Pediatrics, Division of Nephrology, Center for Mitochondrial and Epigenomic Medicine, and Department of Pathology and Laboratory Medicine, Division of Transplant Immunology, and Biesecker Center for Pediatric Liver Disease, Children's Hospital of Philadelphia and University of Pennsylvania; Department of Medicine, Center for Sleep and Circadian Neurobiology, and Department of Physiology and Institute of Diabetes, Obesity, and Metabolism, University of Pennsylvania; and Division of Traumatology and Surgical Critical Care, Hospital of the University of Pennsylvania, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
authors: Douglas C
authors: DC
authors: Wallace
authors: *Department of Pediatrics, Division of Nephrology, Center for Mitochondrial and Epigenomic Medicine, and Department of Pathology and Laboratory Medicine, Division of Transplant Immunology, and Biesecker Center for Pediatric Liver Disease, Children's Hospital of Philadelphia and University of Pennsylvania; Department of Medicine, Center for Sleep and Circadian Neurobiology, and Department of Physiology and Institute of Diabetes, Obesity, and Metabolism, University of Pennsylvania; and Division of Traumatology and Surgical Critical Care, Hospital of the University of Pennsylvania, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
authors: Wayne W
authors: WW
authors: Hancock
mesh_terms: D000818:Animals; D015153:Blotting, Western; D004734:Energy Metabolism / Q000235:genetics / Q000276:immunology*; D051858:Forkhead Transcription Factors / Q000276:immunology* / Q000378:metabolism; D020869:Gene Expression Profiling; D006085:Graft Survival / Q000235:genetics / Q000276:immunology*; D006655:Histone Deacetylases / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D064326:MEF2 Transcription Factors / Q000276:immunology / Q000378:metabolism; D057507:Mice, 129 Strain; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008928:Mitochondria / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D010085:Oxidative Phosphorylation; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D017382:Reactive Oxygen Species / Q000378:metabolism; D012097:Repressor Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D056566:Sirtuin 3 / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000276:immunology / Q000378:metabolism
chemical_list: D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D064326:MEF2 Transcription Factors; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C485290:Ppargc1a protein, mouse; D017382:Reactive Oxygen Species; D012097:Repressor Proteins; C525046:Sirt3 protein, mouse; D014157:Transcription Factors; D056566:Sirtuin 3; C486545:Hdac9 protein, mouse; D006655:Histone Deacetylases
keywords: histone deacetylase; immunity; immunometabolism; immunoregulation; transplant survival