Restoring oxidant signaling suppresses proarthritogenic T cell effector functions in rheumatoid arthritis

Sci Transl Med. 2016 Mar 23;8(331):331ra38. doi: 10.1126/scitranslmed.aad7151.


In patients with rheumatoid arthritis (RA), CD4(+)T cells hyperproliferate during clonal expansion, differentiating into cytokine-producing effector cells that contribute to disease pathology. However, the metabolic underpinnings of this hyperproliferation remain unclear. In contrast to healthy T cells, naïve RA T cells had a defect in glycolytic flux due to the up-regulation of glucose-6-phosphate dehydrogenase (G6PD). Excess G6PD shunted glucose into the pentose phosphate pathway, resulting in NADPH (reduced form of nicotinamide adenine dinucleotide phosphate) accumulation and reactive oxygen species (ROS) consumption. With surplus reductive equivalents, RA T cells insufficiently activated the redox-sensitive kinase ataxia telangiectasia mutated (ATM), bypassed the G2/M cell cycle checkpoint, and hyperproliferated. Moreover, insufficient ATM activation biased T cell differentiation toward the T helper 1 (TH1) and TH17 lineages, imposing a hyperinflammatory phenotype. We have identified several interventions that replenish intracellular ROS, which corrected the abnormal proliferative behavior of RA T cells and successfully suppressed synovial inflammation. Thus, rebalancing glucose utilization and restoring oxidant signaling may provide a therapeutic strategy to prevent autoimmunity in RA.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Arthritis, Rheumatoid / immunology*
  • Arthritis, Rheumatoid / metabolism
  • Arthritis, Rheumatoid / pathology*
  • Ataxia Telangiectasia Mutated Proteins / metabolism
  • Cell Cycle Checkpoints
  • Cell Differentiation
  • Cell Proliferation
  • Free Radical Scavengers / metabolism
  • Glucose / metabolism
  • Glutathione / metabolism
  • Humans
  • Inflammation / pathology
  • NADP / metabolism
  • Oxidants / metabolism*
  • Oxidation-Reduction
  • Pentose Phosphate Pathway
  • Reactive Oxygen Species / metabolism
  • Signal Transduction*
  • Stress, Physiological
  • T-Lymphocytes / immunology*


  • Free Radical Scavengers
  • Oxidants
  • Reactive Oxygen Species
  • NADP
  • Ataxia Telangiectasia Mutated Proteins
  • Glutathione
  • Glucose