Idd9.2 and Idd9.3 Protective Alleles Function in CD4(+) T-Cells and Nonlymphoid Cells to Prevent Expansion of Pathogenic Islet-Specific CD8(+) T-Cells

OBJECTIVE: Multiple type 1 diabetes susceptibility genes have now been identified in both humans and mice, yet mechanistic understanding of how they impact disease pathogenesis is still minimal. We have sought to dissect the cellular basis for how the highly protective mouse Idd9 region limits the expansion of autoreactive CD8(+) T-cells, a key cell type in destruction of the islets. RESEARCH DESIGN AND METHODS: We assess the endogenous CD8(+) T-cell repertoire for reactivity to the islet antigen glucose-6-phosphatase–related protein (IGRP). Through the use of adoptively transferred T-cells, bone marrow chimeras, and reconstituted severe combined immunodeficient mice, we identify the protective cell types involved. RESULTS: IGRP-specific CD8(+) T-cells are present at low frequency in the insulitic lesions of Idd9 mice and could not be recalled in the periphery by viral expansion. We show that Idd9 genes act extrinsically to the CD8(+) T-cell to prevent the massive expansion of pathogenic effectors near the time of disease onset that occurs in NOD mice. The subregions Idd9.2 and Idd9.3 mediated this effect. Interestingly, the Idd9.1 region, which provides significant protection from disease, did not prevent the expansion of autoreactive CD8(+) T-cells. Expression of Idd9 genes was required by both CD4(+) T-cells and a nonlymphoid cell to induce optimal tolerance. CONCLUSIONS: Idd9 protective alleles are associated with reduced expansion of IGRP-specific CD8(+) T-cells. Intrinsic expression of protective Idd9 alleles in CD4(+) T-cells and nonlymphoid cells is required to achieve an optimal level of tolerance. Protective alleles in the Idd9.2 congenic subregion are required for the maximal reduction of islet-specific CD8(+) T-cells.