title: Cytotoxic T-lymphocyte-mediated killing of human pancreatic islet cells in vitro.
abstract: Cytotoxic T lymphocytes (CTL) are believed to play an essential role in beta-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 beta 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 beta 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 beta-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.
authors.affiliation: St Vincent's Institute, The University of Melbourne Department of Medicine, St. Vincent's Hospital, Fitzroy, Australia.
authors.forename: Peter D
authors.initials: PD
authors.lastname: Campbell
authors.forename: Eugene
authors.initials: E
authors.lastname: Estella
authors.forename: Nadine L
authors.initials: NL
authors.lastname: Dudek
authors.forename: Gaurang
authors.initials: G
authors.lastname: Jhala
authors.forename: Helen E
authors.initials: HE
authors.lastname: Thomas
authors.forename: Thomas W H
authors.initials: TW
authors.lastname: Kay
authors.forename: Stuart I
authors.initials: SI
authors.lastname: Mannering
mesh_terms: D045744:Cell Line, Tumor; D002999:Clone Cells / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D003602:Cytotoxicity, Immunologic; D018984:Epitopes, T-Lymphocyte / Q000276:immunology* / Q000378:metabolism; D053222:Fas Ligand Protein / Q000276:immunology / Q000378:metabolism; D006680:HLA Antigens / Q000276:immunology / Q000378:metabolism; D006801:Humans; D007371:Interferon-gamma / Q000494:pharmacology; D007515:Islets of Langerhans / Q000276:immunology* / Q000378:metabolism; D018942:Macrolides / Q000494:pharmacology; D054353:Perforin / Q000276:immunology / Q000378:metabolism; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology / Q000378:metabolism*
chemical_list: D018984:Epitopes, T-Lymphocyte; D053222:Fas Ligand Protein; D006680:HLA Antigens; D018942:Macrolides; D054353:Perforin; C036978:concanamycin A; D007371:Interferon-gamma