The Iddm4 gene controls diabetes in rats depleted of regulatory T cells (T reg) and immune-activated via treatment with the toll-like receptor 3 (TLR-3) ligand, polyI:C. Both diabetes-resistant (BBDR) and diabetes-prone (BBDP) BB rats carry dominant permissive alleles of Iddm4, while the recessive Wistar Furth (WF) rat allele is protective. Iddm4 is positioned close to Iddm2 on chromosome 4, but when we introgressed BBDP-derived parts of this region--either containing both genes or Iddm2 alone--into the WF genome, none of these congenic strains developed spontaneous diabetes. Although both strains harbor two copies of the recessive Iddm2 allele of the BBDP rat, making these animals devoid of T reg cells, immune activation in itself via polyI:C treatment did not induce overt diabetes. Interestingly, TLR-3 ligation without depletion of T regs resulted in diabetes and insulitis development in nonlymphopenic F1-offspring of mating the Iddm4+Iddm2 congenic strain to WF. This demonstrates that the diabetogenic allele of Iddm4 is able to confer diabetes susceptibility even in a nonlymphopenic host with a full T reg pool, and that homozygosity for Iddm2--although responsible for an almost total lack of T regs-delays the disease process. Finally, we have confirmed the position of Iddm4 in truly congenic strains.