MONOCYTES EXPRESS FAS LIGAND UPON CD4 CROSS-LINKING AND INDUCE CD4(-CELLS APOPTOSIS - A POSSIBLE MECHANISM OF BYSTANDER CELL-DEATH IN HIV-INFECTION() T)

Recent evidence indicates that death of uninfected lymphocytes by apop tosis plays an important role in the immunopathogenesis of HIV infecti on. We have previously demonstrated that CD4 cross-linking (CD4XL) per formed in PBMC results in induction of T cell apoptosis in an accessor y cell-dependent manner, In this study, we have investigated the roles of Fas interaction with its ligand (Fast) and of accessory cells in t he CD4XL model of T cell apoptosis mediated by the anti-CD4 mAb Leu3a- or HIV-1 envelope protein g120, Here, we provide evidence that CD4XL- induced CD4(+) T cell apoptosis is Fas-FasL interaction dependent and that monocytes play a critical role in inducing T cell apoptosis, We s how that CD4XL-induced T cell apoptosis is blocked by the addition of soluble Fas or by anti-Fast mAb NOK-1;depletion of monocytes from PBMC , but not of CD19(+) cells or CD8(+) cells, abrogates CD4XL-induced T cell apoptosis. Conversely, addition of monocytes to purified CD4(+) T cells augments CD4XL-induced apoptosis. In purified monocytes, CD4XL results in Fast expression; in purified CD4(+) T cells, however, CD4XL upregulates Fas but not Fast expression. These findings underscore th e important role of monocytes in HIV disease pathogenesis and firmly s upport the notion of CD4XL as a potent mechanism for inducing bystande r cell death.