Loss of NAPDH oxidase-derived superoxide exacerbates diabetogenic CD4 T cell effector responses (BA11P.122)

Abstract

Abstract In Type 1 diabetes (T1D), infiltrating leukocytes secrete reactive oxygen species (ROS) and pro-inflammatory cytokines that participate in β-cell destruction and enhance T cell autoreactivity. We previously demonstrated that superoxide-deficient Non-obese diabetic (NOD.Ncf1m1J) mice were T1D-resistant due, in part, to blunted Th1 CD4 and cytotoxic CD8 T cell responses. To dissect the role of ROS on autoreactive CD4 T cells, we created the NOD.BDC-2.5.Ncf1m1J (BDC-2.5.Ncf1m1J) mouse with diabetogenic, superoxide-deficient CD4 T cells and hypothesized that reducing ROS would diminish autoreactivity. BDC-2.5.Ncf1m1J splenocytes stimulated with the BDC-2.5 mimotope or islets displayed elevated IFN-γ and pro-inflammatory chemokine ligands CXCL10 and CCL5 (p<0.05). BDC-2.5.Ncf1m1J CD4 T cells were more diabetogenic (p=0.002), with only 26% of transferred NOD.Rag (n=45) mice euglycemic at 10 days post transfer, in contrast to 56% of BDC-2.5-transferred mice (n=24). In vivo suppression assays revealed that enhanced diabetogenicity was due to defective Treg activity, as BDC-2.5.Ncf1m1J Tregs curbed T1D in only 33% of BDC-2.5-transferred NOD.Rag mice (n=9), while BDC-2.5 Tregs induced 70% protection (n=10). Our results highlight the intricate role that ROS induce and restrict T1D autoreactivity. Future studies will dissect the TCR adaptor molecule oxidation status in BDC-2.5.Ncf1m1J CD4 T cells, as these targets may reveal novel biomarkers for T1D progression and prevention.