Human β-Cell Killing by Autoreactive Preproinsulin-Specific CD8 T Cells Is Predominantly Granule-Mediated With the Potency Dependent Upon T-Cell Receptor Avidity
- Robin R. Knight1,
- Deborah Kronenberg1,2,
- Min Zhao3,
- Guo Cai Huang3,
- Martin Eichmann1,
- Anna Bulek4,
- Linda Wooldridge4,
- David K. Cole4,
- Andrew K. Sewell4,
- Mark Peakman1,2⇓ and
- Ania Skowera1,2
- 1Department of Immunobiology, King’s College London, London, United Kingdom
- 2National Institute for Health Research comprehensive Biomedical Research Centre, Guy’s and St. Thomas’ National Health Service Foundation Trust and King’s College London, London, United Kingdom
- 3Diabetes and Nutritional Science, King’s College London, London, United Kingdom
- 4Institute of Infection and Immunity, Cardiff University School of Medicine, Cardiff, United Kingdom
- Corresponding author: Mark Peakman, .
M.P. and A.S. contributed equally to this work.
The end-stage immunopathology of type 1 diabetes resulting in β-cell destruction appears to be strongly dominated by cytotoxic CD8 T lymphocytes (CD8 T cells). However, the mechanism of cytotoxicity used by autoreactive CD8 T cells in the human setting remains unknown. Using type 1 diabetes patient–derived preproinsulin-specific CD8 T-cell clones recognizing either an HLA-A2 (A*0201) or HLA-A24 (A*2402)-restricted epitope (peptide of preproinsulin [PPI]15–24, ALWGPDPAAA; or PPI3–11, LWMRLLPLL), we assessed the use of conventional mediators of cytotoxicity in the destruction of human β-cells in vitro compared with virus-specific cytotoxic CD8 T-cell clones. We show that PPI-specific CD8 T-cell clones are mainly reliant upon cytotoxic degranulation for inducing β-cell death. Furthermore, we find that in comparison with virus-specific CD8 T cells, there are differences in the killing potency of PPI-specific CD8 T cells that are not due to cell-intrinsic differences, but rather are mediated by differences in strength of signaling by peptide–HLA ligands. The study highlights the regulation of β-cell killing as a potential point for therapeutic control, including the possibility of blocking autoreactive CD8 T-cell function without impacting upon general immune competence.
This article contains Supplementary Data online at http://diabetes.diabetesjournals.org/lookup/suppl/doi:10.2337/db12-0315/-/DC1.
- Received March 11, 2012.
- Accepted July 7, 2012.
- © 2013 by the American Diabetes Association.
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