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- Title
Human β-cell killing by autoreactive preproinsulin-specific CD8 T cells is predominantly granule-mediated with the potency dependent upon T-cell receptor avidity.
- Authors
Knight RR; Kronenberg D; Zhao M; Huang GC; Eichmann M; Bulek A; Wooldridge L; Cole DK; Sewell AK; Peakman M; Skowera A; Knight, Robin R; Kronenberg, Deborah; Zhao, Min; Huang, Guo Cai; Eichmann, Martin; Bulek, Anna; Wooldridge, Linda; Cole, David K; Sewell, Andrew K
- 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.
- Publication
Diabetes, 2013, Vol 62, Issue 1, p205
- ISSN
0012-1797
- Publication type
journal article
- DOI
10.2337/db12-0315