title: Fas/Fas ligand interaction regulates cytotoxicity of CD4+ T cells against staphylococcal enterotoxin B-pulsed endothelial cells.
abstract: Infiltration of activated CD4+ T cells and apoptosis of endothelial cells are present in the synovium of rheumatoid arthritis (RA). Using staphylococcal enterotoxin B (SEB) as an antigen, we examined the possible role of antigen (Ag)-dependent activation of CD4+ T cells by endothelial cells, in inducing endothelial cell apoptosis. The human endothelial cell line, EA.hy926 cells, was cultured with or without interferon-gamma (IFN-gamma) and further incubated with CD4+ T cells in the presence or absence of SEB. After this cocultivation, the cytotoxicity and Fas ligand (FasL) expression of CD4+ T cells were examined. A small percentage of EA.hy926 cells expressed HLA-DR and -DQ, and this expression was significantly augmented after IFN-gamma stimulation. Anti-Fas IgM-induced apoptosis was exhibited by both unstimulated and IFN-gamma-stimulated EA.hy926 cells. Cytotoxicity of CD4+ T cells toward SEB-pulsed unstimulated EA.hy926 cells was detected. Furthermore, when CD4+ T cells were incubated with IFN-gamma-stimulated, SEB-pulsed EA.hy926 cells with augmented HLA-DR and -DQ expression, this cytotoxicity was more significant. The addition of anti-HLA-DR and -DQ monoclonal antibodies (mAbs) or human Fas chimeric protein (hFas-Fc) reduced the cytotoxicity. FasL expression was induced in CD4+ T cells cocultured with SEB-pulsed EA.hy926 cells, especially when the EA.hy926 cells were IFN-gamma-stimulated. Furthermore, the addition of mAbs against CD54 and CD58 inhibited both the cytotoxicity and FasL expression of CD4+ T cells induced by SEB-pulsed EA.hy926 cells, indicating the importance of costimulatory molecules on EA.hy926 cells in activating CD4+ T cells. Our results suggest that CD4+ T cells are activated by endothelial cells in an Ag-dependent manner and subsequently express FasL, which induces Fas-mediated apoptosis of endothelial cells. This phenomenon may counteract the growth of RA synovium by inhibiting the proliferation of endothelial cells.
authors.affiliation: First Department of Internal Medicine, Nagasaki University School of Medicine, Japan.
authors.forename: S
authors.initials: S
authors.lastname: Urayama
authors.forename: A
authors.initials: A
authors.lastname: Kawakami
authors.forename: N
authors.initials: N
authors.lastname: Matsuoka
authors.forename: M
authors.initials: M
authors.lastname: Tsuboi
authors.forename: T
authors.initials: T
authors.lastname: Nakashima
authors.forename: Y
authors.initials: Y
authors.lastname: Kawabe
authors.forename: T
authors.initials: T
authors.lastname: Koji
authors.forename: K
authors.initials: K
authors.lastname: Eguchi
mesh_terms: D000911:Antibodies, Monoclonal / Q000494:pharmacology; D000954:Antigens, Surface / Q000096:biosynthesis; D017209:Apoptosis / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism*; D018968:CD58 Antigens / Q000276:immunology / Q000378:metabolism; D002460:Cell Line; D002478:Cells, Cultured; D018920:Coculture Techniques; D003602:Cytotoxicity, Immunologic; D004730:Endothelium, Vascular / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D004768:Enterotoxins / Q000276:immunology*; D053222:Fas Ligand Protein; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000276:immunology / Q000378:metabolism; D008024:Ligands; D008562:Membrane Glycoproteins / Q000096:biosynthesis / Q000378:metabolism*; D013211:Staphylococcus aureus / Q000276:immunology; D019014:fas Receptor / Q000276:immunology / Q000378:metabolism
chemical_list: D000911:Antibodies, Monoclonal; D000954:Antigens, Surface; D018968:CD58 Antigens; D004768:Enterotoxins; C505661:FASLG protein, human; D053222:Fas Ligand Protein; D008024:Ligands; D008562:Membrane Glycoproteins; D019014:fas Receptor; D018799:Intercellular Adhesion Molecule-1; C031818:enterotoxin B, staphylococcal