Poster Presentation The 13th International Congress of the Immunology of Diabetes Society 2013

Inhibition of NADPH-oxidase (NOX) derived superoxide in T cells maintains Sirtuin-1 (Sirt-1) activity, oxidative phosphorylation, and T cell hyporesponsiveness. (#108)

Jon D. Piganelli 1 , Dana M. Previte 1 , Meghan L. Marre 1 , Gina M. Coudriet 1 , Massimo M. Trucco 2 , Meghan M. Greenwood 1
  1. Pediatrics/Medicine/Immunology, Children's Hosptial of Pittsburgh of UPMC and University of Pittsburgh School of Medicine , Pittsburgh, PA, United States
  2. Children's Hosptial of Pittsburgh of UPMC, Pittsburgh, PA, United States

In type 1 diabetes (T1D), the generation of reactive oxygen species (ROS) is critical for progression of T cell activation and immune-mediated β cell destruction. Superoxide and H2O2 are generated during T cell activation by NADPH-oxidase (NOX) to facilitate the immune response. NOX is critical in other highly replicating cell types (e.g., cancer cells) to facilitate metabolic program switching from oxidative phosphorylation (naïve, OXPHOS) to aerobic glycolysis (activated, AG). However, NOX’s precise role in T cell metabolic programming and subsequent activation remains poorly defined. To address this we demonstrated that NOD mice incapable of NOX assembly and superoxide synthesis (NOD.Ncf1) are protected from T1D, have reduced respiratory burst, NF-κB-dependent proinflammatory cytokines, and reduced Th1 expansion and effector function. In addition, treatment with a redox modulating manganese metalloporphyrin (MnP) catalytic antioxidant also reduced T cell activation, delayed T1D onset in vivo, and inhibited antigen-specific Th1 effector function and proinflammatory cytokine production. MnP-treated BDC-2.5 T cells demonstrated reduced p-mTOR, c-myc, glucose transporter 1 (Glut1) levels, as well as lactate production, all of which are critical for AG and immune cell activation. We further showed that redox modulation reduced levels of glycolytic enzymes, which indicate reduced switching to AG and T cell activation. In addition, MnP also maintained high levels of  Sirt-1, which increases OXPHOS and maintains immune cell quiescence. Therefore inhibition of NOX-derived ROS may lead to stable Sirt-1 expression, a sustained OXPHOS metabolic program, and T cell hyporesponsiveness. These findings suggest a novel alternative for controlling aberrant self-reactivity by targeting the metabolic processes necessary for immune cell activation.