Chromogranin A (ChgA) is an antigenic target of pathogenic CD4(+) T cells in a non-obese diabetic (NOD) mouse model of type 1 diabetes (T1D). Vasostatin-1 is a naturally processed fragment of ChgA. We have now identified a novel H2-K(d) -restricted epitope of vasostatin-1, ChgA 36-44, which elicits CD8(+) T cell responses in NOD mice. By using ChgA 36-44/K(d) tetramers we have determined the frequency of vasostatin-1-specific CD8(+) T cells in pancreatic islets and draining lymph nodes of NOD mice. We also demonstrate that vasostatin-1-specific CD4(+) and CD8(+) T cells constitute a significant fraction of islet-infiltrating T cells in diabetic NOD mice. Adoptive transfer of T cells from ChgA 36-44 peptide-primed NOD mice into NOD/severe combined immunodeficiency (SCID) mice led to T1D development. These findings indicate that vasostatin-1-specific CD8(+) T cells contribute to the pathogenesis of type 1 diabetes in NOD mice.