Fas/Fas ligand interaction regulates cytotoxicity of CD4+ T cells against staphylococcal enterotoxin B-pulsed endothelial cells.

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.