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Type 1 diabetes (T1D) is a T cell-mediated autoimmune disease that has a strong HLA association, where a number of self-epitopes have been implicated in disease pathogenesis. Human pancreatic islet-infiltrating CD4 + T cell clones not only respond to proinsulin C-peptide (PI 40-54; GQVELGGGPGAGSLQ) but also cross-react with a hybrid insulin peptide (HIP; PI 40-47 -IAPP 74-80; GQVELGGG-NAVEVLK) presented by HLA-DQ8. How T cell receptors recognize self-peptide and cross-react to HIPs is unclear. We investigated the cross-reactivity of the CD4 + T cell clones reactive to native PI 40-54 epitope and multiple HIPs fused at the same N-terminus (PI 40-54 ) to the degradation products of two highly expressed pancreatic islet proteins, neuropeptide Y (NPY 68-74 ) and amyloid polypeptide (IAPP 23-29 and IAPP 74-80 ). We observed that five out of the seven selected SKW3 T cell lines expressing TCRs isolated from CD4 + T cells of people with T1D responded to multiple HIPs. Despite shared TRAV26-1-TRBV5-1 gene usage in some T cells, these clones cross-reacted to varying degrees with the PI 40-54 and HIP epitopes. Crystal structures of two TRAV26-1 + -TRBV5-1 + T cell receptors (TCRs) in complex with PI 40-54 and HIPs bound to HLA-DQ8 revealed that the two TCRs had distinct mechanisms responsible for their differential recognition of the PI 40-54 and HIP epitopes. Alanine scanning mutagenesis of the PI 40-54 and HIPs determined that the P2, P7, and P8 residues in these epitopes were key determinants of TCR specificity. Accordingly, we provide a molecular basis for cross-reactivity towards native insulin and HIP epitopes presented by HLA-DQ8., Competing Interests: Conflict of interest The authors declare that they have no conflicts of interest with the contents of this article., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)