Journal
DIABETES
Volume 61, Issue 7, Pages 1752-1759Publisher
AMER DIABETES ASSOC
DOI: 10.2337/db11-1520
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Funding
- U.K. Department of Health via the National Institute for Health Research Comprehensive Biomedical Research Centre Award
- Juvenile Diabetes Research Foundation [7-2005-877, 1-2007-1803]
- EU
- Diabetes U.K PhD Studentship
- Medical Research Council [MR/J006742/1] Funding Source: researchfish
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Type 1 diabetes results from T cell-mediated beta-cell destruction. The HLA-A*24 class I gene confers significant risk of disease and early onset. We tested the hypothesis that HLA-A24 molecules on islet cells present preproinsulin (PPI) peptide epitopes to CD8 cytotoxic T cells (CTLs). Surrogate beta-cell lines secreting proinsulin and expressing HLA-A24 were generated and their peptide ligandome examined by mass spectrometry to discover naturally processed and HLA-A24-presented PPI epitopes. A novel PPI epitope was identified and used to generate HLA-A24 tetramers and examine the frequency of PPI-specific T cells in new-onset HLA-A*24(+) patients and control subjects. We identified a novel naturally processed and HLA-A24-presented PPI signal peptide epitope (PPI3-11; LWMRLLPLL). HLA-A24 tetramer analysis reveals a significant expansion of PPI3-11-specific CD8 T cells in the blood of HLA-A*24(+) recent-onset patients compared with HLA-matched control subjects. Moreover, a patient-derived PPI3-11-specific CD8 T-cell clone shows a proinflammatory phenotype and kills surrogate beta-cells and human HLA-A*24(+) islet cells in vitro. These results indicate that the type I diabetes susceptibility molecule HLA-A24 presents a naturally processed PPI signal peptide epitope. PPI-specific, HLA-A24-restricted CD8 T cells are expanded in patients with recent-onset disease. Human islet cells process and present PPI3-11, rendering themselves targets for CTL-mediated killing. Diabetes 61:1752-1759, 2012
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