Genetic interactions among Idd3 Idd5.1 Idd5.2 and Idd5.3 protective loci in the NOD mouse model of type 1 diabetes

摘要

In the nonobese diabetic (NOD) mouse model of type 1 diabetes (T1D), insulin-dependent diabetes (Idd) loci control the development of insulitis and diabetes. Independently, protective alleles of Idd3/Il2 or Idd5 are able to partially protect congenic NOD mice from insulitis and diabetes, and to partially tolerize islet-specific CD8+ T cells. However, when the two regions are combined, mice are almost completely protected, strongly suggesting the existence of genetic interactions between the two loci. Idd5 contains at least three protective sub-regions/causative gene candidates, Idd5.1/Ctla4, Idd5.2/Slc11a1 and Idd5.3/Acadl, yet it is unknown which of them interacts with Idd3/Il2. Through the use of a series of novel congenic strains containing the Idd3/Il2 region and different combinations of Idd5 sub-region(s), we defined these genetic interactions. The combination of Idd3/Il2 and Idd5.3/Acadl was able to provide nearly complete protection from T1D, but all three Idd5 sub-regions were required to protect from insulitis and fully restore self-tolerance. By backcrossing a Slc11a1 KO allele onto the NOD genetic background, we have demonstrated that Slc11a1 is responsible for the diabetes protection resulting from Idd5.2. We also used Slc11a1 KO-SCID and Idd5.2-SCID mice to show that both loss-of-function alleles provide protection from insulitis when expressed on the SCID host alone. These results lend further support to the hypothesis that Slc11a1 is Idd5.2.