Insulin-dependent diabetes (IDDM) results from T-cell-dependent autoimmune destruction of the insulin-producing cells in the pancreas. Susceptibility to this disorder is hereditary, but it is clearly not due to a single abnormal gene. In an individual with a susceptible genetic background, the initiation and/or rate of progression of the disease process may be influenced by environmental factors. These characteristics have severely impeded progress in determining the pathogenic mechanism underlying IDDM in humans. Fortunately, two excellent rodent models exist for spontaneous, genetically-controlled autoimmune diabetes: the BB/W rat and the Non-Obese Diabetic (NOD) mouse. Using breeding studies and sophisticated new methods for identifying genes, investigators have demonstrated that the disease process in these animals is polygenic. However, none of the specific genes required have been conclusively identified. In order to identify the genes which cause IDDM, we randomly introduced non-NOD alleles into NOD mice by breeding them with mice from a non-diabetes-prone strain (C57L/J) and selecting for those which could block diabetes. Using this method, we have developed three diabetes-resistant mouse lines. In each resistant line the disease process has been inhibited at a different step. Mice from one of these lines (DR3) have pancreatic inflammation but no insulitis or diabetes. This suggests that we have introduced a healthy version of a gene which controls the development of destructive T cells in these mice. We have localized this gene to the telomeric half of mouse chromosome 11. Although other investigators have demonstrated a weak effect of chromosome 11 loci in earlier breeding studies using other non-diabetes-prone mouse strains as donors, the C57L/J allele of this gene is the most potent inhibitor of disease progression that we have identified. We will show mapping data which localizes this gene to a discrete fragment of chromosome 11 and present data suggesting that this gene contributes to autoimmune susceptibility states by its influence on the presentation of antigens to T cells.