ABSTRACT
Type 1 diabetes (T1D) is characterized by T cell-mediated destruction of the insulin-producing βcells of the pancreatic islets. Among the loci associated with T1D risk, those most predisposing are found in the MHC region. HLA-B*39:06 is the most predisposing class I MHC allele and is associated with an early age of onset. To establish an NOD mouse model for the study of HLA-B*39:06, we expressed it in the absence of murine class I MHC. HLA-B*39:06 was able to mediate the development of CD8 T cells, support lymphocytic infiltration of the islets, and confer T1D susceptibility. Because reduced thymic insulin expression is associated with increased T1D risk in patients, we incorporated this in our model as well, finding that HLA-B*39:06-transgenic NOD mice with reduced thymic insulin expression have an earlier age of disease onset and a higher overall prevalence as compared to littermates with typical thymic insulin expression. This was despite virtually indistinguishable blood insulin levels, T cell subset percentages, and TCR Vβ family usage, indicating that reduced thymic insulin expression does not impact T cell development on a global scale. Rather, we propose that it allows the thymic escape of insulin-reactive HLA-B*39:06-restricted T cells which participate in β cell destruction. We also found that in mice expressing either HLA-B*39:06 or HLA-A*02:01 in the absence of murine class I MHC, HLA transgene identity alters TCR Vβ usage, which may contribute to varying diabetogenic CD8 T cell repertoires in the presence of different HLA class I alleles.
Footnotes
1 This work was supported by the National Institutes of Health (R01 DK064315, R01 DK094327, and R03 AI119225 to T.P.D.; R01 DK046266, R01 DK095735, and U54 OD020351-5022 to D.V.S.; F30 DK103368 to J.S.; F32 DK111078 to J.J.R.; T32 GM007288 which supported J.S.; P30 CA013330 which supports the Cancer Center of the Albert Einstein College of Medicine; P30 CA034196 which supports the Cancer Center of The Jackson Laboratory; and P60 DK020541 which supports the Diabetes Research Center of the Albert Einstein College of Medicine) and the American Diabetes Association (1-16-IBS-069 to T.P.D.). T.P.D. is the Diane Belfer, Cypres & Endelson Families Faculty Scholar in Diabetes Research.
↵2 Address correspondence and reprint requests to Teresa P. DiLorenzo (Department of Microbiology and Immunology, Albert Einstein College of Medicine, 1300 Morris Park Ave., Bronx, NY 10461; E-mail address: teresa.dilorenzo{at}einstein.yu.edu)