Circulating Preproinsulin Signal Peptide–Specific CD8 T Cells Restricted by the Susceptibility Molecule HLA-A24 Are Expanded at Onset of Type 1 Diabetes and Kill β-Cells

• Published in: Diabetes (New York, N.Y.) Vol. 61; no. 7; pp. 1752 - 1759
• Main Authors: Kronenberg, Deborah, Knight, Robin R., Estorninho, Megan, Ellis, Richard J., Kester, Michel G., de Ru, Arnoud, Eichmann, Martin, Huang, Guo C., Powrie, Jake, Dayan, Colin M., Skowera, Ania, van Veelen, Peter A., Peakman, Mark
• Format: Journal Article
• Language: English
• Published: Alexandria, VA American Diabetes Association 01.07.2012
• Subjects: Adult; Analysis; Autoantibodies - blood; Autoantibodies - immunology; Biological and medical sciences; CD8-Positive T-Lymphocytes - immunology; Cell Death - immunology; Cell Line; Diabetes Mellitus, Type 1 - immunology; Diabetes. Impaired glucose tolerance; Endocrine pancreas. Apud cells (diseases); Endocrinopathies; Epitopes, T-Lymphocyte - immunology; Etiopathogenesis. Screening. Investigations. Target tissue resistance; Female; Glutamate Decarboxylase - immunology; HLA class II antigens; HLA-A24 Antigen - immunology; Humans; Immunology and Transplantation; Insulin - blood; Insulin - immunology; Insulin-Secreting Cells - immunology; Male; Medical sciences; Middle Aged; Physiological aspects; Protein Precursors - blood; Protein Precursors - immunology; Protein Sorting Signals; T cells; Type 1 diabetes; Young Adult; Endocrinopathy; Immunopathology; HLA-System; Sensitivity; Peptides; Type 1 diabetes; Langerhans islet; T-Lymphocyte; Autoimmune disease; β Cell; Endocrine pancreas
• ISSN: 0012-1797; 1939-327X; 1939-327X
• DOI: 10.2337/db11-1520

Type 1 diabetes results from T cell-mediated β-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 β-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 (PPI(3-11); LWMRLLPLL). HLA-A24 tetramer analysis reveals a significant expansion of PPI(3-11)-specific CD8 T cells in the blood of HLA-A*24(+) recent-onset patients compared with HLA-matched control subjects. Moreover, a patient-derived PPI(3-11)-specific CD8 T-cell clone shows a proinflammatory phenotype and kills surrogate β-cells and human HLA-A*24(+) islet cells in vitro. These results indicate that the type 1 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 PPI(3-11), rendering themselves targets for CTL-mediated killing.