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In Vivo Cytotoxicity of Insulin-specific CD8⁺ T Cells in HLA-A*0201-transgenic NOD Mice

¹Department of Microbiology and Immunology and
²Department of Medicine (Division of Endocrinology), Albert Einstein College of Medicine, Bronx, NY 10461
³Department of Pediatrics, Division of Genetic and Translational Medicine, University of Alabama at Birmingham, Birmingham, AL 35294
⁴The Jackson Laboratory, Bar Harbor, ME 04609

Correspondence: dilorenz{at}aecom.yu.edu

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 diabetes 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 utilized islet-infiltrating CD8⁺ T cells from HLA-A*0201-transgenic NOD mice in an IFN- 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 five weeks of age, suggesting an important function for these specificities early in the pathogenic process. Though 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 diabetes patients.

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