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
- Deborah Kronenberg1,2,
- Robin R. Knight2,
- Megan Estorninho2,
- Richard J. Ellis2,
- Michel G. Kester3,
- Arnoud de Ru4,
- Martin Eichmann2,
- Guo C. Huang5,
- Jake Powrie1,6,
- Colin M. Dayan7,
- Ania Skowera1,2,
- Peter A. van Veelen4 and
- Mark Peakman1,2⇓
- 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.
- 2Department of Immunobiology, King’s College London, London, U.K.
- 3Department of Hematology, Leiden University Medical Centre, Leiden, the Netherlands
- 4Department of Immunohematology and Blood Transfusion, Leiden University Medical Centre, Leiden, the Netherlands
- 5Division of Diabetes and Nutritional Science, King’s College London, London, U.K.
- 6Department of Diabetes and Endocrinology, Guy’s and St. Thomas’ Hospital National Health Service Foundation Trust, U.K.
- 7Department of Medicine, Cardiff University, Cardiff, Wales, U.K.
- Corresponding author: Mark Peakman, .
P.A.vV. and M.P. contributed equally to this study.
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.
- © 2012 by the American Diabetes Association.
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