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Cell Metab. 2017 Jun 6;25(6):1282-1293.e7. doi: 10.1016/j.cmet.2016.12.018. Epub 2017 Apr 13.

Foxp3 Reprograms T Cell Metabolism to Function in Low-Glucose, High-Lactate Environments.

Author information

1
Center for Mitochondrial and Epigenomic Medicine, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
2
Penn 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.
3
Division 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.
4
Division of Nephrology and Department of Pediatrics, Children's Hospital of Philadelphia and University of Pennsylvania, Philadelphia, PA 19104, USA.
5
Department of Surgery, Penn Transplant Institute, Perelman School of Medicine, Children's Hospital of Philadelphia and University of Pennsylvania, Philadelphia, PA 19104, USA.
6
Department of Physiology and Institute of Diabetes, Obesity, and Metabolism, University of Pennsylvania, Philadelphia, PA 19104, USA.
7
Center 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.
8
Center 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.
9
Division 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.

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.

KEYWORDS:

T cell metabolism; immune regulation; immunometabolism

PMID:
28416194
PMCID:
PMC5462872
DOI:
10.1016/j.cmet.2016.12.018
[Indexed for MEDLINE]
Free PMC Article

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