期刊
JOURNAL OF IMMUNOLOGY
卷 184, 期 2, 页码 658-665出版社
AMER ASSOC IMMUNOLOGISTS
DOI: 10.4049/jimmunol.0903414
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资金
- National Institutes of Health [R01 DK064315, P01 DK052956, P60 DK020541]
- Juvenile Diabetes Research Foundation
- Irma T. Hirschl/Monique Weill-Caulier Trust
- National Institutes of Health Cancer Center [P30 CA013330]
Type 1 diabetes results from the autoimmune destruction of insulin-producing beta cells by T cells specific for beta 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 1diabetes-associated HLA-A*0201 (designated NOD.beta 2m(-/-).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.beta 2m(-/-).HRD.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.beta 2m(-/-).HRD.Ins2(-/-) strain as an improved humanized disease model, in particular for studies seeking to develop therapeutic strategies targeting insulin-specific T cells. The Journal of Immunology, 2010, 184: 658-665.
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