Reduced numbers of dendritic cells with a tolerogenic phenotype in the prediabetic pancreas of NOD mice

The NOD mouse is a widely used animal model of autoimmune diabetes. Prior to the onset of lymphocytic insulitis, DCs accumulate at the islet edges. Our recent work indicated that these DCs may derive from aberrantly proliferating local precursor cells. As CD8 alpha(+) DCs play a role in tolerance induction in steady-state conditions, we hypothesized that the autoimmune phenotype might associate with deficiencies in CD8 alpha(+) DCs in the prediabetic NOD mouse pancreas. We studied CD8 alpha(+) DCs in the pancreas and pLNs of NOD and control mice, focusing on molecules associated with tolerance induction (CD103, Langerin, CLEC9A, CCR5). mRNA expression levels of tolerance-modulating cytokines were studied in pancreatic CD8 alpha(+) DCs of NOD and control mice. In the NOD pancreas, the frequency of CD8 alpha(+)CD103(+)Langerin(+) cells was reduced significantly compared with control mice. NOD pancreatic CD8 alpha(+)CD103(+)Langerin(+) DCs expressed reduced levels of CCR5, CLEC9A, and IL-10 as compared with control DCs. These alterations in the CD8 alpha(+)CD103(+)Langerin(+) DC population were not present in pLNs. We demonstrate local abnormalities in the CD8 alpha(+) DC population in the prediabetic NOD pancreas. These data suggest that abnormal differentiation of pancreatic DCs contributes to loss of tolerance, hallmarking the development of autoimmune diabetes. J. Leukoc. Biol. 92: 1207-1213; 2012.