Journal
EUROPEAN JOURNAL OF IMMUNOLOGY
Volume 45, Issue 9, Pages 2494-2503Publisher
WILEY-BLACKWELL
DOI: 10.1002/eji.201445378
Keywords
Autoimmune diabetes; CD4(+) T cells; MHC class II; Pancreatic beta cell
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Funding
- National Health and Medical Research Council of Australia (NHMRC) [APP1061961, APP1037321]
- NHMRC
- JDRF
- Operational Infrastructure Support Scheme of the Government of Victoria
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Type 1 diabetes results from destruction of pancreatic beta cells by autoreactive T cells. Both CD4(+) and CD8(+) T cells have been shown to mediate beta-cell killing. While CD8(+) T cells can directly recognize MHC class I on beta cells, the interaction between CD4(+) T cells and beta cells remains unclear. Genetic association studies have strongly implicated HLA-DQ alleles in human type 1 diabetes. Here we studied MHC class II expression on beta cells in nonobese diabetic mice that were induced to develop diabetes by diabetogenic CD4(+) T cells with T-cell receptors that recognize beta-cell antigens. Acute infiltration of CD4(+) T cells in islets occurred with rapid onset of diabetes. Beta cells from islets with immune infiltration expressed MHC class II mRNA and protein. Exposure of beta cells to IFN-gamma increased MHC class II gene expression, and blocking IFN-gamma signaling in beta cells inhibited MHC class II upregulation. IFN-gamma also increased HLA-DR expression in human islets. MHC class II+ beta cells stimulated the proliferation of beta-cell-specific CD4(+) T cells. Our study indicates that MHC class II molecules may play an important role in beta-cell interaction with CD4(+) T cells in the development of type 1 diabetes.
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