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.
Original language | English |
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Pages (from-to) | 205-13 |
Number of pages | 9 |
Journal | Diabetes |
Volume | 62 |
Issue number | 1 |
DOIs | |
Publication status | Published - Jan 2013 |
Keywords
- Antigens, CD95
- CD8-Positive T-Lymphocytes
- Cell Degranulation
- Cell Line
- Cytotoxicity, Immunologic
- Fas Ligand Protein
- Humans
- Insulin
- Insulin-Secreting Cells
- Protein Precursors
- Receptors, Antigen, T-Cell
- Tumor Necrosis Factor-alpha