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Immunology and Transplantation

Human β-Cell Killing by Autoreactive Preproinsulin-Specific CD8 T Cells Is Predominantly Granule-Mediated With the Potency Dependent Upon T-Cell Receptor Avidity

  1. Robin R. Knight1,
  2. Deborah Kronenberg1,2,
  3. Min Zhao3,
  4. Guo Cai Huang3,
  5. Martin Eichmann1,
  6. Anna Bulek4,
  7. Linda Wooldridge4,
  8. David K. Cole4,
  9. Andrew K. Sewell4,
  10. Mark Peakman1,2⇓ and
  11. Ania Skowera1,2
  1. 1Department of Immunobiology, King’s College London, London, United Kingdom
  2. 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
  3. 3Diabetes and Nutritional Science, King’s College London, London, United Kingdom
  4. 4Institute of Infection and Immunity, Cardiff University School of Medicine, Cardiff, United Kingdom
  1. Corresponding author: Mark Peakman, mark.peakman{at}kcl.ac.uk.
  1. M.P. and A.S. contributed equally to this work.

Diabetes 2013 Jan; 62(1): 205-213. https://doi.org/10.2337/db12-0315
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Abstract

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.

Footnotes

  • 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.

Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. See http://creativecommons.org/licenses/by-nc-nd/3.0/ for details.

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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. Knight, Deborah Kronenberg, Min Zhao, Guo Cai Huang, Martin Eichmann, Anna Bulek, Linda Wooldridge, David K. Cole, Andrew K. Sewell, Mark Peakman, Ania Skowera
Diabetes Jan 2013, 62 (1) 205-213; DOI: 10.2337/db12-0315

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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. Knight, Deborah Kronenberg, Min Zhao, Guo Cai Huang, Martin Eichmann, Anna Bulek, Linda Wooldridge, David K. Cole, Andrew K. Sewell, Mark Peakman, Ania Skowera
Diabetes Jan 2013, 62 (1) 205-213; DOI: 10.2337/db12-0315
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