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.
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.
authors.affiliation: Department of Immunobiology, King’s College London, London, United Kingdom.
authors.forename: Robin R
authors.initials: RR
authors.lastname: Knight
authors.forename: Deborah
authors.initials: D
authors.lastname: Kronenberg
authors.forename: Min
authors.initials: M
authors.lastname: Zhao
authors.forename: Guo Cai
authors.initials: GC
authors.lastname: Huang
authors.forename: Martin
authors.initials: M
authors.lastname: Eichmann
authors.forename: Anna
authors.initials: A
authors.lastname: Bulek
authors.forename: Linda
authors.initials: L
authors.lastname: Wooldridge
authors.forename: David K
authors.initials: DK
authors.lastname: Cole
authors.forename: Andrew K
authors.initials: AK
authors.lastname: Sewell
authors.forename: Mark
authors.initials: M
authors.lastname: Peakman
authors.forename: Ania
authors.initials: A
authors.lastname: Skowera
mesh_terms: D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D015550:Cell Degranulation; D002460:Cell Line; D003602:Cytotoxicity, Immunologic; D053222:Fas Ligand Protein / Q000502:physiology; D006801:Humans; D007328:Insulin / Q000276:immunology*; D050417:Insulin-Secreting Cells / Q000473:pathology*; D011498:Protein Precursors / Q000276:immunology*; D011948:Receptors, Antigen, T-Cell / Q000502:physiology*; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology; D019014:fas Receptor / Q000502:physiology
chemical_list: C505661:FASLG protein, human; D053222:Fas Ligand Protein; D007328:Insulin; D011498:Protein Precursors; D011948:Receptors, Antigen, T-Cell; D014409:Tumor Necrosis Factor-alpha; D019014:fas Receptor; C013737:preproinsulin