Loss of NADPH oxidase-derived superoxide induces CD4 T cell antigen-specific hyporesponsiveness by modulating IL-12 signaling (IRM5P.637)

Abstract

Abstract Efficient T cell adaptive immune activation requires innate immune-derived reactive oxygen species (ROS) and pro-inflammatory cytokines. Our laboratory previously demonstrated blunted CD4 T cell autoreactivity in the absence of NADPH oxidase (NOX)-derived superoxide, as NOX-deficient Non-obese diabetic (NOD.Ncf1m1J) mice exhibited spontaneous Type 1 diabetes-resistance, partly due to decreased Th1 cytokine responses. To examine the role of ROS deficiency on antigen-specific T cells in a non-autoimmune setting and further test the hypothesis that ROS exacerbates Th1 T cell responses, we generated the OT-II.Ncf1m1J mouse containing superoxide-deficient OVA323-339-specific CD4 T cells. Stimulated OT-II.Ncf1m1J splenocytes displayed decreased Th1 T cell cytokines IFN-γ and TNF-α (p<0.05) and diminished expression of the Th1 transcription factor T-bet and Th1 signal transducer IL-12Rβ2, compared to OT-II CD4 T cells. IFN-γ synthesis and IL-12 signaling by OT-II.Ncf1m1J T cells were rescued by addition of exogenous superoxide and co-culture with superoxide-sufficient antigen-presenting cells; conversely, Th1 responses were blunted in wild type OT-II T cells via free radical dissipation with a superoxide dismutase mimetic. This data highlights the importance of NOX-derived ROS in providing a third signal for adaptive immune maturation by modulating IL-12 signaling and implicates that targeting ROS may represent a promising therapeutic strategy in curbing CD4 T cell autoreactivity.