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

  1. Mark Peakman1,2
  1. 1National 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, U.K.
  2. 2Department of Immunobiology, King’s College London, London, U.K.
  3. 3Department of Hematology, Leiden University Medical Centre, Leiden, the Netherlands
  4. 4Department of Immunohematology and Blood Transfusion, Leiden University Medical Centre, Leiden, the Netherlands
  5. 5Division of Diabetes and Nutritional Science, King’s College London, London, U.K.
  6. 6Department of Diabetes and Endocrinology, Guy’s and St. Thomas’ Hospital National Health Service Foundation Trust, U.K.
  7. 7Department of Medicine, Cardiff University, Cardiff, Wales, U.K.
  1. Corresponding author: Mark Peakman, mark.peakman{at}kcl.ac.uk.
  1. P.A.vV. and M.P. contributed equally to this study.

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 (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 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 PPI3–11, rendering themselves targets for CTL-mediated killing.

  • Received October 28, 2011.
  • Accepted March 2, 2012.

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  1. Diabetes
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