Monocytes express Fas ligand upon CD4 cross-linking and induce CD4+ T cells apoptosis: a possible mechanism of bystander cell death in HIV infection

Abstract

Recent evidence indicates that death of uninfected lymphocytes by apoptosis plays an important role in the immunopathogenesis of HIV infection. We have previously demonstrated that CD4 cross-linking (CD4XL) performed in PBMC results in induction of T cell apoptosis in an accessory cell-dependent manner. In this study, we have investigated the roles of Fas interaction with its ligand (FasL) and of accessory cells in the 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 show that CD4XL-induced T cell apoptosis is blocked by the addition of soluble Fas or by anti-FasL 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 FasL expression; in purified CD4+ T cells, however, CD4XL upregulates Fas but not FasL expression. These findings underscore the important role of monocytes in HIV disease pathogenesis and firmly support the notion of CD4XL as a potent mechanism for inducing bystander cell death.