Abstract: T Cell Responses to Hybrid Insulin Peptides as Biomarkers of Disease Activity in Type 1 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 characterize T cell responses to HIPs in the PBMCs of T1D and controls; (2) to determine the extent of reactivity to insulin B:9-23 Hybrid Insulin Peptides in recent onset T1D patients; (3) Investigate the presence and phenotype of HIP-reactive T cells in the natural history of T1D.