In vivo cytotoxicity of insulin-specific CD8+ T-cells in HLA-A*0201 transgenic NOD mice.

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CD8-Positive-T-Lymphocytes, Cytotoxicity-Immunologic, Female, HLA-A-Antigens, Humans, Insulin, Islets-of-Langerhans, Mice-Inbred-NOD, Mice-Knockout, Mice-Transgenic, Recombinant-Fusion-Proteins

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Diabetes 2007 Oct; 56(10):2551-60.


OBJECTIVE: CD8(+) T-cells specific for islet antigens are essential for the development of type 1 diabetes in the NOD mouse model of the disease. Such T-cells can also be detected in the blood of type 1 diabetic patients, suggesting their importance in the pathogenesis of the human disease as well. The development of peptide-based therapeutic reagents that target islet-reactive CD8(+) T-cells will require the identification of disease-relevant epitopes. RESEARCH DESIGN AND METHODS: We used islet-infiltrating CD8(+) T-cells from HLA-A*0201 transgenic NOD mice in an interferon-gamma enzyme-linked immunospot assay to identify autoantigenic peptides targeted during the spontaneous development of disease. We concentrated on insulin (Ins), which is a key target of the autoimmune response in NOD mice and patients alike. RESULTS: We found that HLA-A*0201-restricted T-cells isolated from the islets of the transgenic mice were specific for Ins1 L3-11, Ins1 B5-14, and Ins1/2 A2-10. Insulin-reactive T-cells were present in the islets of mice as young as 5 weeks of age, suggesting an important function for these specificities early in the pathogenic process. Although there was individual variation in peptide reactivity, Ins1 B5-14 and Ins1/2 A2-10 were the immunodominant epitopes. Notably, in vivo cytotoxicity to cells bearing these peptides was observed, further confirming them as important targets of the pathogenic process. CONCLUSIONS: The human versions of B5-14 and A2-10, differing from the murine peptides by only a single residue, represent excellent candidates to explore as CD8(+) T-cell targets in HLA-A*0201-positive type 1 diabetic patients.