Superoxide production by macrophages and T cells is critical for the induction of autoreactivity and type 1 diabetes

Academic Article

Abstract

  • OBJECTIVE - The role of reactive oxygen species (ROS) and their dissipation in type 1 diabetes pathogenesis have garnered considerable controversy. Our recent work has demonstrated the importance of NADPH oxidase (NOX) activity for type 1 diabetes development and modulating T-cell autoreactivity. We previously linked decreased monocyte ROS with diabetes resistance in the alloxan-resistant mouse, and NOD-Ncf1m1J mice with a genetic ablation of NOX activity had reduced and delayed type 1 diabetes compared with NOD mice. RESEARCH DESIGN AND METHODS - To determine the required cellular sources of ROS that are necessary for type 1 diabetes initiation, we used antibody depletion and adoptive transfer experiments into NOD and NOD-Scid females, respectively. After receiving treatment, female mice were monitored for hyperglycemia and overt diabetes. RESULTS - Depletion of macrophages and neutrophils fully protected NOD mice from type 1 diabetes. However, elimination of neutrophils alone showed no significant reduction or delay. Type 1 diabetes induction in NOD-Scid mice by adoptive transfer with NOD-Ncf1m1J splenocytes was significantly delayed compared with NOD splenocytes, suggesting macrophage ROS and modulation of effector responses are critical for diabetes. The adaptive immune response was also altered by the absence of NOX activity, as purified T cells from NOD-Ncf1m1J mice exhibited delayed transfer kinetics. Cotransfer experiments demonstrated the defect was intrinsic to NOX-deficient CD8 + T cells. After stimulation, cytotoxic T cells exhibited decreased effector function in the absence of superoxide production. CONCLUSIONS - These data demonstrate that the impaired autoreactive response of NOX-deficient NOD-Ncf1m1J immune system results from an alteration in the antigen-presenting cell-T-cell axis rather than failure of neutrophils to act as effector cells and that ROS signaling is important for the initiation of β-cell-directed autoimmunity by T cells. © 2011 by the American Diabetes Association.
  • Authors

    Published In

  • Diabetes  Journal
  • Digital Object Identifier (doi)

    Author List

  • Thayer TC; Delano M; Liu C; Chen J; Padgett LE; Tse HM; Annamali M; Piganelli JD; Moldawer LL; Mathews CE
  • Start Page

  • 2144
  • End Page

  • 2151
  • Volume

  • 60
  • Issue

  • 8