Transgenic rescue implicates β(2)-microglobulin as a diabetes susceptibility gene in nonobese diabetic (NOD) mice

Type 1 diabetes in both humans and nonobese diabetic (NOD) mice results from T-cell-mediated autoimmune destruction of insulin-producing pancreatic β cells. Linkage studies have shown that type 1 diabetes in NOD mice is a polygenic disease involving more than 15 chromosomal susceptibility regions. Despite extensive investigation, the identification of individual susceptibility genes either within or outside the major histocompatibility complex region has proven problematic because of the limitations of linkage analysis. In this paper, we provide evidence implicating a single diabetes susceptibility gene, which lies outside the major histocompatibility complex region. Using allelic reconstitution by transgenic rescue, we show that NOD mice expressing the β(2) microglobulin (β(2)M)(a) allele develop diabetes, whereas NOD mice expressing a murine β(2)M(b) or human allele are protected. The murine β(2)M(a) allele differs from the β(2)M(b) allele only at a single amino acid. Mechanistic studies indicate that the absence of the NOD β(2)M(a) isoform on nonhematopoietic cells inhibits the development or activation of diabetogenic T cells.