Through regulation of TCR expression levels, an Idd7 region gene(s) interactively contributes to the impaired thymic deletion of autoreactive diabetogenic CD8+ T cells in nonobese diabetic mice.

When expressed in NOD, but not C57BL/6 (B6) genetic background mice, the common class I variants encoded by the H2(g7) MHC haplotype aberrantly lose the ability to mediate the thymic deletion of autoreactive CD8(+) T cells contributing to type 1 diabetes (T1D). This indicated some subset of the T1D susceptibility (Idd) genes located outside the MHC of NOD mice interactively impair the negative selection of diabetogenic CD8(+) T cells. In this study, using both linkage and congenic strain analyses, we demonstrate contributions from a polymorphic gene(s) in the previously described Idd7 locus on the proximal portion of Chromosome 7 predominantly, but not exclusively, determines the extent to which H2(g7) class I molecules can mediate the thymic deletion of diabetogenic CD8(+) T cells as illustrated using the A14 TCR transgenic system. The polymorphic Idd7 region gene(s) appears to control events that respectively result in high vs low expression of the A14 clonotypic TCR alpha-chain on developing thymocytes in B6.H2(g7) and NOD background mice. This expression difference likely lowers levels of the clonotypic A14 TCR in NOD, but not B6.H2(g7) thymocytes, below the threshold presumably necessary to induce a signaling response sufficient to trigger negative selection upon Ag engagement. These findings provide further insight to how susceptibility genes, both within and outside the MHC, may interact to elicit autoreactive T cell responses mediating T1D development in both NOD mice and human patients.