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 ORCID: https://orcid.org/0000-0003-0028-9396, Sewell, Andrew K. ORCID: https://orcid.org/0000-0003-3194-3135, 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:	24 Oct 2022 10:10
URI:	https://orca.cardiff.ac.uk/id/eprint/43314

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