Loss of NOX-derived superoxide exacerbates diabetogenic CD4 T-cell effector responses in type 1 diabetes

Academic Article

Abstract

  • © 2015 by the American Diabetes Association. Reactive oxygen species (ROS) play prominent roles in numerous biological systems. While classically expressed by neutrophils and macrophages, CD4 T cells also express NADPH oxidase (NOX), the superoxide-generating multisubunit enzyme. Our laboratory recently demonstrated that superoxide-deficient nonobese diabetic (NOD. Ncf1m1J) mice exhibited a delay in type 1 diabetes (T1D) partially due to blunted IFN-γ synthesis by CD4 T cells. For further investigation of the roles of superoxide on CD4 T-cell diabetogenicity, the NOD.BDC-2.5.Ncf1m1J (BDC-2.5.Ncf1m1J) mouse strain was generated, possessing autoreactive CD4 T cells deficient in NOX-derived superoxide. Unlike NOD.Ncf1m1J, stimulated BDC-2.5.Ncf1m1J CD4 T cells and splenocytes displayed elevated synthesis of Th1 cytokines and chemokines. Superoxide-deficient BDC- 2.5 mice developed spontaneous T1D, and CD4 T cells were more diabetogenic upon adoptive transfer into NOD.Rag recipients due to a skewing toward impaired Treg suppression. Exogenous superoxide blunted exacerbated Th1 cytokines and proinflammatory chemokines to approximately wild-type levels, concomitant with reduced IL-12Rβ2 signaling and P-STAT4 (Y693) activation. These results highlight the importance of NOX-derived superoxide in curbing autoreactivity due, in part, to control of Treg function and as a redox-dependent checkpoint of effector T-cell responses. Ultimately, our studies reveal the complexities of free radicals in CD4 T-cell responses.
  • Authors

    Published In

  • Diabetes  Journal
  • Digital Object Identifier (doi)

    Author List

  • Padgett LE; Anderson B; Liu C; Ganini D; Mason RP; Piganelli JD; Mathews CE; Tse HM
  • Start Page

  • 4171
  • End Page

  • 4183
  • Volume

  • 64
  • Issue

  • 12