Ins2 deficiency augments spontaneous HLA-A*0201-restricted T Cell responses to insulin

Irene Jarchum, Teresa P. DiLorenzo

Research output: Contribution to journalArticle

13 Scopus citations

Abstract

Type 1 diabetes results from the autoimmune destruction of insulin-producing β cells by T cells specific for β cell Ags, including insulin. In humans, the non-MHC locus conferring the strongest disease susceptibility is the insulin gene, and alleles yielding lower thymic insulin expression are predisposing. We sought to incorporate this characteristic into an HLA-transgenic model of the disease and to determine the influence of reduced thymic insulin expression on CD8+ T cell responses to preproinsulin. We examined NOD.Ins2-/- mice, which do not express insulin in the thymus and show accelerated disease, to determine whether they exhibit quantitative or qualitative differences in CD8+ T cell responses to preproinsulin. We also generated NOD.Ins2-/- mice expressing type 1 diabetes-associated HLA-A*0201 (designated NOD.β2m -/-.HHD.Ins2-/-) in an effort to obtain an improved humanized disease model. We found that CD8+ T cell reactivity to certain insulin peptides was more readily detected in NOD.Ins2-/- mice than in NOD mice. Furthermore, the proportion of insulin-reactive CD8 + T cells infiltrating the islets of NOD.Ins2-/- mice was increased. NOD.β2m-/-.HHD.Ins2-/- mice exhibited rapid onset of disease and had an increased proportion of HLA-A*0201- restricted insulin-reactive T cells, including those targeting the clinically relevant epitope Ins B10-18. Our results suggest that insulin alleles that predispose to type 1 diabetes in humans do so, at least in part, by facilitating CD8+ T cell responses to the protein. We propose the NOD.β2m-/-.HHD.Ins2-/- strain as an improved humanized disease model, in particular for studies seeking to develop therapeutic strategies targeting insulin-specific T cells.

Original languageEnglish (US)
Pages (from-to)658-665
Number of pages8
JournalJournal of Immunology
Volume184
Issue number2
DOIs
StatePublished - Jan 15 2010

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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