W hile CD8⁺ T cells are critical to diabetogenesis in NOD mice, evidence of their involvement in human type 1 diabetes (T1D) has been circumstantial. The existence of CD8⁺ T cells specific for β cell peptides has been demonstrated, but functional data regarding the role of these cells in T1D have been lacking. In this issue of the JCI, Skowera et al. describe an unusual self-peptide epitope derived from the leader sequence of preproinsulin (PPI) and show that 50% of HLA-A2⁺ patients with new-onset T1D possessed circulating CD8⁺ T cells specific for this epitope, suggesting that PPI plays a critical role in the development of T1D (see the related article beginning on page 3390). They also report that β cells upregulate PPI expression in the presence of high glucose levels, rendering these cells more susceptible to lysis and potentially accelerating disease. This suggests that interventions aimed at decreasing the PPI-specific CD8⁺ T cell response early after T1D diagnosis may be efficacious in ameliorating the disease process.