Antigen presentation in Type 1 diabetes: Routes to pathogenesis and prevention

Abstract

Type 1 diabetes (Ti D) is characterized by T cell mediated destruction of the insulin-producing beta cells in the pancreatic islets. T cells require the presentation of beta cell epitopes on MHC molecules in order to target the beta cells. This presentation occurs both by the beta cells themselves, as well as by professional antigen presenting cells, such as dendritic cells (DCs). To understand Ti D pathogenesis and develop effective therapies to prevent disease, it is essential to understand the interaction of antigen presenting cells with autoreactive T cells.;Multiple genetic loci have been found to be associated with Ti D risk, with those most predisposing to disease found in the MHC region. Among the class I MHC alleles found to be predisposing to T1 D is HLA-B*39:06. HLA-B*39:06 has only recently been identified as a predisposing allele and much remains to be understood about its ability to confer Ti D risk. HLAB*39:06 is the most predisposing class I MHC allele and is associated with an early age of onset but has only been studied via genome-wide association studies. We therefore established a non-obese diabetic (NOD) mouse model for the study of HLA-B*3906 by expressing HLA-B*39:06 in the absence of murine class I MHC. HLA-B*39:06 was able to mediate the development of CD8 T cells in these mice and was able to confer Ti D susceptibility and infiltration of the pancreatic islets. Because Ti D patients display reduced thymic insulin expression, which is associated with increased disease risk, we incorporated this in our model as well, finding that HLA-B*39:06transgenic NOD mice with reduced thymic insulin expression have an earlier age of disease onset as compared to littermates with typical insulin expression. This was despite indistinguishable insulin production and T cell development, suggesting that autoreactivity to insulin is responsible for an earlier age of onset. Weak peptide-MHC interactions are often associated with the development of autoimmunity. To examine this possibility, we compared the peptide binding capabilities of HLA-B*39:06 to HLA-B*39:01, which has similar anchor residue preferences and is also associated with T1D risk. We found that HLA-B*39:06 allows for more displacement of resident peptide than HLA-B*39:01, and is less able to bind to 8mer peptides, suggesting that HLA-B*39:06 is less stable and has a more limited repertoire than HLA-B*39:01. HLA-B*39:06 binds poorly to potential insulin epitopes, suggesting the formation of weak peptide-MHC molecules which can allow for the escape of insulin-specific T cells. We find insulin-specific CD8 T cells in the islets of HLA-B*39:06-transgenic NOD mice with reduced thymic insulin expression. We therefore propose that poor peptide binding by HLA-B*39:06, combined with decreased thymic insulin expression, allows for the escape of HLA-B*39:06-restricted insulin-specific CD8 T cells and the development of Ti D.;Delivery of beta cell antigens to DCs in a tolerogenic manner can result in T cell tolerance towards beta cells. Delivery of epitopes to DCs using DC endocytic receptors can lead to CD4 and CD8 T cell tolerance, both of which are important to Ti D pathogenesis. To create a more clinically relevant model for DC-targeted therapies, we developed NOD mice with transgenic expression of human DEC-205 (hDEC). These mice were susceptible to disease and the presence of the transgene did not impact DC development or maturation. DCs from hDECtransgenic NOD mice were able to process and present peptide to T cells. Delivery of insulin, linked to anti-hDEC, resulted in antigen presentation to islet-infiltrating T cells, showing that hDEC functions as expected in hDEC-transgenic NOD mice. These mice are therefore a useful model for the preclinical study of dendritic cell-targeted therapies for Ti D.