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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 Mice¹

David V. Serreze^2,*, Caroline Morgane Choisy-Rossi^*, Alexandra E. Grier^*, T. Mathew Holl^*, Harold D. Chapman^*, J. Reed Gahagan^*, Melissa A. Osborne^*, Weidong Zhang^*, Benjamin L. King^*, Aaron Brown, Derry Roopenian^* and Michele P. Marron

^* The Jackson Laboratory, Bar Harbor, ME 04609; Bar Harbor Biotechology Incorporated, Trenton, ME 04605; and Department of Pediatrics, Division of Genetic and Translational Medicine, University of Alabama, Birmingham, AL 35233

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 AI4 TCR transgenic system. The polymorphic Idd7 region gene(s) appears to control events that respectively result in high vs low expression of the AI4 clonotypic TCR -chain on developing thymocytes in B6.H2^g7 and NOD background mice. This expression difference likely lowers levels of the clonotypic AI4 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.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by National Institutes of Health Grants DK51090 and DK46266, Cancer Center Support Grant CA34196, and grants from the Juvenile Diabetes Research Foundation.

² Address correspondence and reprint requests to Dr. David V. Serreze, Senior Staff Scientist, The Jackson Laboratory, Bar Harbor, ME 04609. E-mail address: dave.serreze{at}jax.org

³ Abbreviations used in this paper: T1D, type 1 diabetes; DP, double positive; SNP, single nucleotide polymorphisms; AP, allophycocyanin; QTL, quantitative trait loci; MFI, mean fluorescence intensity; PPD, posterior probability density; LOD, logarithm of odds; Chr., chromosome.