Unmasking Genes in a Type 1 Diabetes–Resistant Mouse Strain That Enhances Pathogenic CD8 T-Cell Responses

OBJECTIVE: Nominally resistant mouse strains such as C57BL/6 (B6) harbor latent type 1 diabetes susceptibility genes uncovered in outcross to disease-susceptible NOD mice. However, identification of possible recessively acting B6-derived susceptibility genes is limited because very few F2 progeny derived from outcrossing this strain with NOD develop spontaneous autoimmune diabetes. Thus, we assessed whether a transgenic T-cell receptor (TCR) disease transfer model allowed the mapping of recessively acting B6 genetic loci that in the proper context contribute to diabetes. RESEARCH DESIGN AND METHODS: CD8 T-cells transgenically expressing the diabetogenic AI4 TCR were transferred into 91 (NODxB6.H2(g7))F1xB6.H2(g7) first-backcross (BC1) females. A genome-wide scan was performed for loci affecting clinical diabetes and insulitis severity. RESULTS: A major locus on chromosome 11 in tight linkage with the marker D11Mit48 (logarithm of odds score = 13.2) strongly determined whether BC1 progeny were susceptible to AI4 T-cell–mediated diabetes. Mice homozygous versus heterozygous for B6 markers of this chromosome 11 genetic locus were, respectively, highly susceptible or resistant to AI4-induced insulitis and diabetes. The genetic effect is manifest by host CD4 T-cells. Microarray analyses of mRNA transcript expression identified a limited number of candidate genes. CONCLUSIONS: The distal region of chromosome 11 in B6 mice harbors a previously unrecognized recessively acting gene(s) that can promote autoreactive diabetogenic CD8 T-cell responses. Future identification of this gene(s) may further aid the screening of heterogeneous humans at future risk for diabetes, and might also provide a target for possible disease interventions.