Human β-cell killing by autoreactive preproinsulin-specific CD8 T cells is predominantly granule-mediated with the potency dependent upon T-cell receptor avidity

Robin R Knight, Deborah Kronenberg, Min Zhao, Guo Cai Huang, Martin Eichmann, Anna Bulek, Linda Wooldridge, David K Cole, Andrew K Sewell, Mark Peakman, Ania Skowera

Research output: Contribution to journalArticle (Academic Journal)peer-review

36 Citations (Scopus)

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 languageEnglish
Pages (from-to)205-13
Number of pages9
JournalDiabetes
Volume62
Issue number1
DOIs
Publication statusPublished - 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

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