title: An anergic cytotoxic T lymphocyte clone exhibits granule exocytosis-mediated cytotoxicity.
abstract: T cell receptor (TCR) occupancy in the absence of a costimulatory signal transforms T helper (Th) cells or cytotoxic T lymphocytes (CTL) into a state of anergy. The anergic T cells are unable to produce cytokines; nevertheless, they maintain their killing activity. We investigated the mechanisms through which anergic CTL causes lysis of target cells. Treatment of a CTL clone with phorbol myristate acetate and calcium ionophore A23187 (P/A) transformed these cells to anergic cells. While the anergic CTL clones failed to secrete TNF-alpha in the culture supernatant, they were still able to kill antigen-specific target cells via a granule exocytosis-mediated pathway. This was evident by the synthesis of perforin mRNA and release of N-alpha-benzyloxycarbonyl-L-lysine thiobenzyl ester esterase by these cells. The anergic CTL clone also showed a low degree of Fas-mediated lysis of normal target cells. In addition, we generated anergic bulk CTL by treatment with P/A and observed that the anergic bulk CTL failed to produce TNF upon antigen stimulation, but retained target killing activity via a granule exocytosis mechanism. Our results suggest that the killing mechanisms of anergic CTL are mediated to a large extent by a granule exocytosis-mediated pathway.
authors.affiliation: Department of Microbiology, Kurume University School of Medicine, Fukuoka, Japan.
authors.forename: K
authors.initials: K
authors.lastname: Kuwano
authors.forename: A
authors.initials: A
authors.lastname: Akashi
authors.forename: S
authors.initials: S
authors.lastname: Arai
mesh_terms: D000818:Animals; D000001:Calcimycin / Q000494:pharmacology; D017635:Clonal Anergy / Q000187:drug effects / Q000276:immunology*; D002999:Clone Cells; D003594:Cytoplasmic Granules / Q000201:enzymology / Q000276:immunology*; D003602:Cytotoxicity, Immunologic / Q000276:immunology*; D005089:Exocytosis / Q000276:immunology*; D053222:Fas Ligand Protein; D053804:Granzymes; D008024:Ligands; D012515:Mast-Cell Sarcoma / Q000276:immunology; D008562:Membrane Glycoproteins / Q000235:genetics; D051379:Mice; D008807:Mice, Inbred BALB C; D054353:Perforin; D052899:Pore Forming Cytotoxic Proteins; D012333:RNA, Messenger / Q000096:biosynthesis; D012697:Serine Endopeptidases / Q000378:metabolism; D013602:T-Lymphocytes, Cytotoxic / Q000187:drug effects / Q000201:enzymology / Q000276:immunology*; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics; D019014:fas Receptor / Q000378:metabolism / Q000502:physiology
chemical_list: D053222:Fas Ligand Protein; C505658:Fasl protein, mouse; D008024:Ligands; D008562:Membrane Glycoproteins; D052899:Pore Forming Cytotoxic Proteins; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D019014:fas Receptor; D054353:Perforin; D000001:Calcimycin; D053804:Granzymes; D012697:Serine Endopeptidases; D013755:Tetradecanoylphorbol Acetate