Research ArticleAutoimmunity

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

Science Translational Medicine  23 Mar 2016:
Vol. 8, Issue 331, pp. 331ra38
DOI: 10.1126/scitranslmed.aad7151

You are currently viewing the abstract.

View Full Text

Via your Institution

Log in through your institution

Log in through your institution


A glucose balancing act

In autoimmune diseases, T cells engage their hyperdrive—both proliferating and secreting inflammatory cytokines at greater rates than in healthy individuals. Yet little is known about the metabolic changes that fuel this process. Now, Yang et al. report that a lack of reactive oxygen species (ROS) could boost proinflammatory T cells in rheumatoid arthritis. They found that a deviation in glycolytic flux led to increased ROS consumption, which bypassed a cell cycle checkpoint and contributed to hyperproliferation and proinflammatory cell differentiation. What’s more, restoring intracellular ROS corrected this abnormal proliferation and suppressed inflammation. Thus, rebalancing glucose utilization and restoring ROS may help treat rheumatoid arthritis.

Abstract

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.

View Full Text