HLA-B*39:06 Efficiently Mediates Type 1 Diabetes in a Mouse Model Incorporating Reduced Thymic Insulin Expression

Abstract

Type 1 diabetes (T1D) is characterized by T cell-mediated destruction of the insulin-producing β cells 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 impaired immunological tolerance to insulin and 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 with littermates with typical thymic insulin expression. This was despite virtually indistinguishable blood insulin levels, T cell subset percentages, and TCR Vβ family usage, confirming that reduced thymic insulin expression does not impact T cell development on a global scale. Rather, it will facilitate 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 by CD8 T cells, demonstrating that some TCR Vβ families have a preference for particular class I MHC alleles.

HLA-B*13, B*35 and B*39 Alleles Are Closely Associated With the Lack of Response to ART in HIV Infection: A Cohort Study in a Population of Northern Brazil

“…This attempt at an immune rebound is consistent with reports that show an association of B*39 with slower disease progression due to epitopes with fitness costs to the virus ( 48 , 49 ). A possible justification is that the cellular response restricted to the allele tends to be more robust and substantial, resulting in improved effector activity with impacts on clinical aspects ( 50 , 51 ).…”

A Humanized Mouse Strain That Develops Spontaneously Immune-Mediated Diabetes

“…Mouse models have been developed that express T1D susceptibility HLA class I ( 65 , 66 ) or class II genes ( 31 , 67 ). They allow defining epitopes on murine autoantigens that possibly correspond to epitopes recognized on human autoantigen along human T1D ( 37 , 54 ).…”

Preclinical Models to Evaluate the Human Response to Autoantigen and Antigen-Specific Immunotherapy in Human Type 1 Diabetes

“…Challenging HLA-DR4/RIP-B7.1 mice with murine proinsulin-2 peptides accelerated T1D development ( 46 ). The level of thymic insulin 2 gene expression determined the timing and the incidence of T1D in an HLA-B*39:06 transgenic mouse, a similar effect of that of the invalidation of the insulin 2 gene in NOD mice ( 47 ) or of the insulin variable number of tandem repeats (VNTR)in humans ( 22 ).…”

“…H2 class-I genes have been invalidated by deleting either the murine β2m or the MHC class-I locus. On the NOD genetic background, mice expressing HLA-A2.1 or HLA-B39 transgenes developed accelerated T1D ( 19 – 22 ) while the expression of HLA-DQ6 decreased the incidence of spontaneous diabetes and insulitis ( 23 , 24 ). HLA-DQ8 or HLA-DR4 transgenic NOD mice depleted for IAg 7 were resistant to diabetes probably because T cells shift toward a tolerogenic regulatory profile ( 25 ).…”