The mechanistic basis bywhich the H2g7 major histocompatibility complex (MHC) provides the primary risk factor for the development of T cell-mediated autoimmune type 1 diabetes (T1D) in non-obese diabetic (NOD) mice involves contributions not only fromthe unusual Ag7 class II molecule, but also from the more common Kd and/or Db class I variants it encodes. Similarly, transgenic studies in NOD mice have confirmed the possibility first suggested in association studies that in the proper genetic context the common human HLA-A2.1 class I variant can mediate diabetogenic CD8 T cell responses. T1D continues to develop in a further refined NOD stock that expresses human HLA-A2.1, but no murine class I molecules (designated NOD.β2m-.HHD). Islet-specific glucose-6-phosphatase catalytic subunit-related protein (IGRP) is an important antigenic target of diabetogenic CD8 cells in standard NOD mice. Three IGRP-derived peptides have also been identified that are presented by human HLA-A2.1 molecules to diabetogenic CD8 T cells in NOD.β2m-.HHD mice. At least one of these IGRP peptides (265-273) can also be the target of autoreactive CD8 T cells in HLA-A2.1-expressing human T1D patients. Studies are currently under way to determine whether HLA-A2.1-restricted IGRP peptides can be used in a tolerance-inducing protocol that inhibits T1D development in NOD. β2m-.HHD mice. If so, this knowledge could ultimately lead to the development of a similar T1D prevention protocol in humans.