Glutathione Primes T Cell Metabolism for Inflammation

Immunity. 2017 Apr 18;46(4):675-689. doi: 10.1016/j.immuni.2017.03.019.


Activated T cells produce reactive oxygen species (ROS), which trigger the antioxidative glutathione (GSH) response necessary to buffer rising ROS and prevent cellular damage. We report that GSH is essential for T cell effector functions through its regulation of metabolic activity. Conditional gene targeting of the catalytic subunit of glutamate cysteine ligase (Gclc) blocked GSH production specifically in murine T cells. Gclc-deficient T cells initially underwent normal activation but could not meet their increased energy and biosynthetic requirements. GSH deficiency compromised the activation of mammalian target of rapamycin-1 (mTOR) and expression of NFAT and Myc transcription factors, abrogating the energy utilization and Myc-dependent metabolic reprogramming that allows activated T cells to switch to glycolysis and glutaminolysis. In vivo, T-cell-specific ablation of murine Gclc prevented autoimmune disease but blocked antiviral defense. The antioxidative GSH pathway thus plays an unexpected role in metabolic integration and reprogramming during inflammatory T cell responses.

Keywords: GSH; Gclc; Myc; NFAT; ROS; T cells; glutathione; glycolysis; mTOR; metabolic reprogramming; metabolism; reactive oxygen species.

MeSH terms

  • Animals
  • Encephalomyelitis, Autoimmune, Experimental / genetics
  • Encephalomyelitis, Autoimmune, Experimental / metabolism
  • Energy Metabolism / genetics
  • Glutamate-Cysteine Ligase / deficiency*
  • Glutamate-Cysteine Ligase / genetics
  • Glutamine / metabolism
  • Glutathione / metabolism*
  • Glycolysis
  • Immunoblotting
  • Inflammation / genetics
  • Inflammation / metabolism*
  • Mice, Inbred C57BL
  • Mice, Knockout
  • NFATC Transcription Factors / metabolism
  • Proto-Oncogene Proteins c-myc / metabolism
  • Reactive Oxygen Species / metabolism
  • Signal Transduction / genetics
  • T-Lymphocytes / metabolism*
  • TOR Serine-Threonine Kinases / metabolism


  • Myc protein, mouse
  • NFATC Transcription Factors
  • Proto-Oncogene Proteins c-myc
  • Reactive Oxygen Species
  • Glutamine
  • mTOR protein, mouse
  • TOR Serine-Threonine Kinases
  • Glutamate-Cysteine Ligase
  • Glutathione