Abstract: T cells reactive to Hybrid Insulin Peptides (HIPs) as biomarkers of autoimmune diabetes An important objective in T1D research is the investigation of autoantigens that activate effector T cells and trigger the inflammatory process in islet beta-cells. We recently identified Hybrid Insulin Peptides (HIPs) as a new class of autoantigens in type 1 diabetes (T1D). These neoantigens are created by the fusion of insulin fragments with peptides from other secretory granule proteins such as chromogranin A (ChgA), islet amyloid polypeptide (IAPP), neuropeptide Y (NPY) or insulin itself. Because insulin is present only in pancreatic beta cells, this discovery might provide an explanation for organ-specific autoimmunity in T1D. Importantly, CD4 T cells responding to HIPs have been isolated from the islets of deceased T1D patients, demonstrating the relevance of these autoantigens to the human disease. We hypothesize that T cells reactive to HIPs can serve as biomarkers of disease. Our goals in this project are (1) to determine the HIP-reactive repertoire of CD4 T cells in NOD mice and (2) to determine the immunophenotype of HIP-reactive T cells in the PBMCs of T1D patients and controls. We will pursue these goals by analyzing T cell reactivity to a panel of HIP peptides in the NOD mouse model of T1D and by testing HLA-DQ8 tetramers loaded with HIP peptides for use in monitoring and selecting HIP-reactive T cells.