The cartography of β-cell epitopes recognized by autoreactive CD8+ T cells has revealed the wide heterogeneity of the autoimmune targets recognized in different T1D patients. We recently described a HLA-A2-restricted ZnT8 epitope which emerged as a notable exception, being recognized in 73% of new-onset T1D patients, both adults and children. Potential reasons for this exceptional immunodominance have been investigated and may reside in inefficient negative selection in the thymus and cross-reactivity with homologous epitopes derived from common infectious agents. Such immunodominant epitopes may offer novel therapeutic opportunities as more universal vaccinal agents that may be delivered to the thymus to boost defective central tolerance. Vaccination strategies targeting this first thymic check point during fetal and neonatal life have been tested in mouse models and shown to confer T1D protection.