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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

Knight, Robin R., Kronenberg, Deborah, Zhao, Min, Huang, Guo Cai, Eichmann, Martin, Bulek, Anna Marta, Wooldridge, Linda, Cole, David, Sewell, Andrew K., Peakman, Mark and Skowera, Ania 2013. Human β-cell killing by autoreactive preproinsulin-specific cd8 t cells is predominantly granule-mediated with the potency dependent upon t-cell receptor avidity. Diabetes 62 (1) , pp. 205-213. 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 PPI(3-11), 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.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Medicine
Systems Immunity Research Institute (SIURI)
Subjects: R Medicine > R Medicine (General)
R Medicine > RC Internal medicine
Publisher: American Diabetes Association
ISSN: 0012-1797
Last Modified: 04 Jun 2017 04:42
URI: http://orca.cf.ac.uk/id/eprint/43314

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