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

Jennifer Schloss, Riyasat Ali, Jeremy J. Racine, Harold D. Chapman, David V. Serreze, Teresa P. DiLorenzo

Research output: Contribution to journalArticle

3 Scopus citations

Abstract

Type 1 diabetes (T1D) is characterized by T cell–mediated destruction of the insulin-producing b 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 Vb 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 b 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 Vb usage by CD8 T cells, demonstrating that some TCR Vb families have a preference for particular class I MHC alleles.

Original languageEnglish (US)
Pages (from-to)3353-3363
Number of pages11
JournalJournal of Immunology
Volume200
Issue number10
DOIs
StatePublished - May 15 2018

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ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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