The goal of this research project is to identify self-reactive T cell clones and monitor the frequency and activation state during the progression of autoimmune diabetes. Identification of T-cell reactivity to beta-cell antigen epitopes is important to study pathogenesis and monitor antigen specific interventions in T1D. We have successfully generated and validated human tetramer reagents to diabetes relevant target antigens to determine frequency and activation state of autoreactive CD4+ T cells in patients with diabetes. Tetramer reagents could provide much needed biomarker reagents to predict T1D earlier in ‘at risk’ patients, stage clinical disease, and determine if therapeutic approaches have an effect on the CD4+ T cell level during T1D pathogenesis. If successful, the tetramer biomarkers and enrichment approach we are testing could precede autoantibody production and provide an earlier diagnosis of T1D, before irreparable damage has occurred to the islets. Therefore, these reagents would have great impact to provide a new in vivo diagnostic approach to identify T1D T cell responses as an early diagnosis for high risk patients. With a better understanding of beta cell specific targets we will be able to develop novel therapeutic approaches to cure diabetes.