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

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


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.

MeSH terms

  • Animals
  • Cell Line
  • Cellular Microenvironment / genetics
  • Cellular Microenvironment / immunology*
  • Cellular Reprogramming / genetics
  • Cellular Reprogramming / immunology*
  • Forkhead Transcription Factors / genetics
  • Forkhead Transcription Factors / immunology*
  • Glucose / genetics
  • Glucose / immunology*
  • Glycolysis / genetics
  • Glycolysis / immunology
  • Humans
  • Lactic Acid / immunology*
  • Mice
  • Mice, Inbred BALB C
  • Mice, Knockout
  • Oxidative Phosphorylation
  • Proto-Oncogene Proteins c-myc / genetics
  • Proto-Oncogene Proteins c-myc / immunology
  • T-Lymphocytes, Regulatory / immunology*


  • Forkhead Transcription Factors
  • Foxp3 protein, mouse
  • Myc protein, mouse
  • Proto-Oncogene Proteins c-myc
  • Lactic Acid
  • Glucose