title: 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.
abstract: 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.
authors.affiliation: National Institute for Health Research Comprehensive Biomedical Research Centre at Guy’s and St. Thomas’ National Health Service Foundation Trust and King’s College London, London, UK.
authors.forename: Deborah
authors.initials: D
authors.lastname: Kronenberg
authors.forename: Robin R
authors.initials: RR
authors.lastname: Knight
authors.forename: Megan
authors.initials: M
authors.lastname: Estorninho
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Ellis
authors.forename: Michel G
authors.initials: MG
authors.lastname: Kester
authors.forename: Arnoud
authors.initials: A
authors.lastname: de Ru
authors.forename: Martin
authors.initials: M
authors.lastname: Eichmann
authors.forename: Guo C
authors.initials: GC
authors.lastname: Huang
authors.forename: Jake
authors.initials: J
authors.lastname: Powrie
authors.forename: Colin M
authors.initials: CM
authors.lastname: Dayan
authors.forename: Ania
authors.initials: A
authors.lastname: Skowera
authors.forename: Peter A
authors.initials: PA
authors.lastname: van Veelen
authors.forename: Mark
authors.initials: M
authors.lastname: Peakman
mesh_terms: D000328:Adult; D001323:Autoantibodies / Q000097:blood / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D016923:Cell Death / Q000276:immunology; D002460:Cell Line; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology*; D018984:Epitopes, T-Lymphocyte / Q000276:immunology; D005260:Female; D005968:Glutamate Decarboxylase / Q000276:immunology; D059871:HLA-A24 Antigen / Q000276:immunology*; D006801:Humans; D007328:Insulin / Q000097:blood / Q000276:immunology*; D050417:Insulin-Secreting Cells / Q000276:immunology*; D008297:Male; D008875:Middle Aged; D011498:Protein Precursors / Q000097:blood / Q000276:immunology*; D021382:Protein Sorting Signals; D055815:Young Adult
chemical_list: D001323:Autoantibodies; D018984:Epitopes, T-Lymphocyte; D059871:HLA-A24 Antigen; D007328:Insulin; D011498:Protein Precursors; D021382:Protein Sorting Signals; C013737:preproinsulin; D005968:Glutamate Decarboxylase