Type 1 diabetes (T1D) occurs because of lack of T cell tolerance to islet antigens. We hypothesized that critical genetic susceptibility loci that control progression to T1D, designated as insulin-dependent diabetes (Idd) loci, would be responsible for preventing CD8 T cell tolerance. To test this hypothesis, we have used two different congenic non-obese diabetic (NOD) mice that are highly protected from the occurrence of T1D because they express protective alleles at Idd3 and Idd5.1, 5.2, 5.3 (Idd3/5 mice), or at Idd9.1, 9.2, and 9.3 (Idd9 mice). By examining the CD8 T response to two different islet-expressed antigens, we have determined that CD8 T tolerance is restored in both strains of mice. However, tolerance occurs at different checkpoints in each strain. In Idd3/5 mice, islet-antigen-specific CD8 T cells are eliminated in the pancreatic lymph nodes, where they are first activated by cross-presented islet antigens. In contrast, in Idd9 mice autoreactive CD8 T cells accumulate at this site and are not tolerized until after they enter the pancreas. We are currently identifying the cell types and mechanisms that are critical for tolerance induction at each checkpoint.