Idd1 and Idd3 are necessary but not sufficient for development of type 1 diabetes in NOD mouse

Type 1 diabetes in the NOD mouse is under polygenic control, with a major susceptibility gene, Idd1, in the major histocompatibility complex (MHC). To investigate the contribution of the NOD MHC to type 1 diabetes susceptibility, a B6.NOD-H-2 congenic strain, in which the NOD MHC was introgressed onto the genetic background of the C57BL/6 strain, was established. Despite possession of the diabetogenic MHC from the NOD mouse, none of the B6.NOD-H-2 mice developed type 1 diabetes, indicating that the NOD MHC alone is not sufficient for type 1 diabetes and that non-MHC genes are also necessary. One of the strongest non-MHC genes is Idd3, and Il2 which encodes interleukin 2, is a candidate gene for Idd3. To test whether a combination of the NOD MHC with the NOD allele of Il2 is sufficient for type 1 diabetes, B6.NOD-H-2 mice were crossed with C3H mice, which possess the NOD allele at Il2, and F2 mice homozygous for NOD alleles at both the MHC and Il2 were produced. None of the F2 mice developed type 1 diabetes, suggesting that NOD alleles at MHC (Idd1) and Il2 (Idd3) are not sufficient for type 1 diabetes in the NOD mouse.