Schematic representation of major autoantigen classes that may be targeted by CD4⁺ T cells. Similar to CD8⁺ T cells, these may include native antigens and neoepitopes, which may be formed under conditions of β cell inflammation and stress. β Cells can produce several neoepitopes: for example, peptides originating from alternative splicing, insulin hybrid peptides (HP), and DRiP insulin peptides are reportedly produced in β cells (for DRiPs, the evidence is from studies of cell lines). Many autoantigens are secretory granule proteins, which may be released by β cells and acquired by APCs. Exosomes released by β cells also contain autoantigens. CD4⁺ T cells may react with antigens captured, processed, and presented by APCs in the pancreatic lymph node and in the islets. The B:9–23 epitope is produced in the secretory granules, captured, and presented by APCs, at least in the NOD mouse. The generation of neoepitopes in β cells further raises the question of whether the previously reported aberrant expression of HLA class II molecules by β cells might allow CD4⁺ T cells to recognize antigens on their surface directly.