Cytotoxic T-lymphocyte–mediated killing of human pancreatic islet cells in vitro

SummaryCytotoxic T lymphocytes (CTL) are believed to play an essential role in β-cell destruction leading to development of type 1 diabetes and allogeneic islet graft failure. We aimed to identify the mechanisms used by CTL to kill human β cells. CTL clones that recognize epitopes from influenza virus and Epstein-Barr virus restricted by human leukocyte antigen (HLA)–A0201 and -B0801, respectively, were used to investigate the susceptibility of human β cells to CTL. In a short-term (5-hour) assay, CTL killed human islet cells of the appropriate major histocompatibility complex (MHC) class I type that had been pulsed with viral peptides. Killing was increased by pretreating islets with interferon gamma that increases MHC class I on target cells. Killing was abolished by incubation of CTL with the perforin inhibitor concanamycin A. The Fas pathway did not contribute to killing because blocking with neutralizing anti–Fas ligand antibody did not significantly reduce β-cell killing. In conclusion, we report a novel way of investigating the interaction between CTL and human islets. Human islets were rapidly killed in vitro by MHC class I–restricted CTL predominantly by the granule exocytosis pathway.