ArticleCell metabolism2017
Foxp3 Reprograms T Cell Metabolism to Function in Low-Glucose, High-Lactate Environments.
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Article in Cell metabolism, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 820 papers.
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820 citing papers in PubMed, 1,139 citations in OpenAlex.
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Authors and funding
20 authors at 3 institutions in 1 country.
Alessia AngelinCenter for Mitochondrial and Epigenomic Medicine, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
Luis Gil-de-GómezPenn SRP Center, Center of Excellence in Environmental Toxicology and Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
Satinder DahiyaDivision of Transplant Immunology, Department of Pathology and Laboratory Medicine, and Biesecker Center for Pediatric Liver Disease, Children's Hospital of Philadelphia and University of Pennsylvania, Philadelphia, PA 19104, USA.
Jing JiaoDivision of Nephrology and Department of Pediatrics, Children's Hospital of Philadelphia and University of Pennsylvania, Philadelphia, PA 19104, USA.
Lili GuoPenn SRP Center, Center of Excellence in Environmental Toxicology and Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
Matthew H LevineDepartment of Surgery, Penn Transplant Institute, Perelman School of Medicine, Children's Hospital of Philadelphia and University of Pennsylvania, Philadelphia, PA 19104, USA.
Zhonglin WangDepartment of Surgery, Penn Transplant Institute, Perelman School of Medicine, Children's Hospital of Philadelphia and University of Pennsylvania, Philadelphia, PA 19104, USA.
William J QuinnDepartment of Physiology and Institute of Diabetes, Obesity, and Metabolism, University of Pennsylvania, Philadelphia, PA 19104, USA.
Piotr K KopinskiCenter for Mitochondrial and Epigenomic Medicine, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA; Howard Hughes Medical Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
Liqing WangDivision of Transplant Immunology, Department of Pathology and Laboratory Medicine, and Biesecker Center for Pediatric Liver Disease, Children's Hospital of Philadelphia and University of Pennsylvania, Philadelphia, PA 19104, USA.
Tatiana AkimovaDivision of Transplant Immunology, Department of Pathology and Laboratory Medicine, and Biesecker Center for Pediatric Liver Disease, Children's Hospital of Philadelphia and University of Pennsylvania, Philadelphia, PA 19104, USA.
Yujie LiuDivision of Transplant Immunology, Department of Pathology and Laboratory Medicine, and Biesecker Center for Pediatric Liver Disease, Children's Hospital of Philadelphia and University of Pennsylvania, Philadelphia, PA 19104, USA.
Tricia R BhattiDivision of Transplant Immunology, Department of Pathology and Laboratory Medicine, and Biesecker Center for Pediatric Liver Disease, Children's Hospital of Philadelphia and University of Pennsylvania, Philadelphia, PA 19104, USA.
Rongxiang HanDivision of Transplant Immunology, Department of Pathology and Laboratory Medicine, and Biesecker Center for Pediatric Liver Disease, Children's Hospital of Philadelphia and University of Pennsylvania, Philadelphia, PA 19104, USA.
Benjamin L LaskinDivision of Nephrology and Department of Pediatrics, Children's Hospital of Philadelphia and University of Pennsylvania, Philadelphia, PA 19104, USA.
Joseph A BaurDepartment of Physiology and Institute of Diabetes, Obesity, and Metabolism, University of Pennsylvania, Philadelphia, PA 19104, USA.
Ian A BlairPenn SRP Center, Center of Excellence in Environmental Toxicology and Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
Douglas C WallaceCenter for Mitochondrial and Epigenomic Medicine, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA; Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
Wayne W HancockDivision of Transplant Immunology, Department of Pathology and Laboratory Medicine, and Biesecker Center for Pediatric Liver Disease, Children's Hospital of Philadelphia and University of Pennsylvania, Philadelphia, PA 19104, USA.
Ulf H BeierDivision of Nephrology and Department of Pediatrics, Children's Hospital of Philadelphia and University of Pennsylvania, Philadelphia, PA 19104, USA. Electronic address: beieru@email.chop.edu.
Children's Hospital of Philadelphia · USUniversity of Pennsylvania · USTranslational Therapeutics (United States) · US
Funding
UNIVERSITY OF PENNSYLVANIA CAN CTR SUPPORT GRANTP30CA016520 · NCI · UNIVERSITY OF PENNSYLVANIA · PI SHELLEY L BERGER · 1985 to 2026
$222.3MVIRAL VECTOR COREP30DK019525 · NIDDK · UNIVERSITY OF PENNSYLVANIA · PI MITCHELL A. LAZAR · 1986 to 2026
$48.3MTransgenic and mutant animalP01AI073489 · NIAID · UNIVERSITY OF PENNSYLVANIA · PI KATSUMATA, MAKOTO · 2008 to 2012
$7.1MMITOCHONDRIAL INBORN ERRORS OF METABOLISMR01NS021328 · NINDS · UNIVERSITY OF CALIFORNIA-IRVINE · PI WALLACE, DOUGLAS C · 1985 to 2017
$6.5MTargeting NAD Metabolism to Improve Glucose Homeostasis in Obesity and AgingR01DK098656 · NIDDK · UNIVERSITY OF PENNSYLVANIA · PI Joseph A. Baur · 2013 to 2026
$6.1MA MITOCHONDRIAL-INTERNEURONAL HYPOTHESIS OF AUTISMR01MH108592 · NIMH · CHILDREN'S HOSP OF PHILADELPHIA · PI WALLACE, DOUGLAS C · 2016 to 2020
$3.1MMouse models for mitochondrial disorders caused by mutations in mtDNAR01OD010944 · OD · UNIVERSITY OF SOUTH ALABAMA · PI ALEXEYEV, MIKHAIL F., WALLACE, DOUGLAS C · 2012 to 2020
$2.6MHDAC2 Inhibition Mitigates Renal Ischemia Reperfusion InjuryR01DK106243 · NIDDK · UNIVERSITY OF PENNSYLVANIA · PI LEVINE, MATTHEW HOWARD · 2016 to 2020
$1.8MHigh-throughput on-chip platform for interrogation of mitochondrial membrane potential and apoptosisR33CA182384 · NCI · UNIVERSITY OF CALIFORNIA-IRVINE · PI BURKE, PETER J. · 2015 to 2017
$1.2MHistone/Protein Deacetylase Inhibitors Minimize Renal Ischemia-Reperfusion InjuryK08DK092282 · NIDDK · UNIVERSITY OF PENNSYLVANIA · PI LEVINE, MATTHEW HOWARD · 2011 to 2015
$768kImmune dysregulation and kidney disease after hematopoietic cell transplantK23DK101600 · NIDDK · CHILDREN'S HOSP OF PHILADELPHIA · PI LASKIN, BENJAMIN LEWIS · 2015 to 2018
$715kTargeting Sirtuin-1 to enhance Foxp3+ regulatory T-cell functionK08AI095353 · NIAID · CHILDREN'S HOSP OF PHILADELPHIA · PI BEIER, ULF · 2011 to 2015
$650kNCI NIH HHS P30 CA016520NCI NIH HHS R33 CA182384NIAID NIH HHS K08 AI095353NIAID NIH HHS P01 AI073489NIAID NIH HHS R01 AI073938NIAID NIH HHS R56 AI095276NIDDK NIH HHS K08 DK092282NIDDK NIH HHS K23 DK101600NIDDK NIH HHS P30 DK019525NIDDK NIH HHS R01 DK098656NIDDK NIH HHS R01 DK106243NIH HHS R01 OD010944NIMH NIH HHS R01 MH108592NINDS NIH HHS R01 NS021328
Abstract
Immune cells function in diverse metabolic environments. Tissues with low glucose and high lactate concentrations, such as the intestinal tract or ischemic tissues, frequently require immune responses to be more pro-tolerant, avoiding unwanted reactions against self-antigens or commensal bacteria. T-regulatory cells (Tregs) maintain peripheral tolerance, but how Tregs function in low-glucose, lactate-rich environments is unknown. We report that the Treg transcription factor Foxp3 reprograms T cell metabolism by suppressing Myc and glycolysis, enhancing oxidative phosphorylation, and increasing nicotinamide adenine dinucleotide oxidation. These adaptations allow Tregs a metabolic advantage in low-glucose, lactate-rich environments; they resist lactate-mediated suppression of T cell function and proliferation. This metabolic phenotype may explain how Tregs promote peripheral immune tolerance during tissue injury but also how cancer cells evade immune destruction in the tumor microenvironment. Understanding Treg metabolism may therefore lead to novel approaches for selective immune modulation in cancer and autoimmune diseases.
Indexed as
AnimalsCell LineCellular MicroenvironmentCellular ReprogrammingForkhead Transcription FactorsGlucoseGlycolysisHumansLactic AcidMiceMice, Inbred BALB CMice, KnockoutOxidative PhosphorylationProto-Oncogene Proteins c-mycT-Lymphocytes, RegulatoryForkhead Transcription FactorsFoxp3 protein, mouseGlucoseLactic AcidMyc protein, mouseProto-Oncogene Proteins c-mycimmune regulationimmunometabolismT cell metabolism
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