title: 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.
authors.affiliation: Department of Pediatrics, North Shore University Hospital-Cornell University Medical College, Manhasset, NY 11030, USA.
authors.forename: N
authors.initials: N
authors.lastname: Oyaizu
authors.forename: Y
authors.initials: Y
authors.lastname: Adachi
authors.forename: F
authors.initials: F
authors.lastname: Hashimoto
authors.forename: T W
authors.initials: TW
authors.lastname: McCloskey
authors.forename: N
authors.initials: N
authors.lastname: Hosaka
authors.forename: N
authors.initials: N
authors.lastname: Kayagaki
authors.forename: H
authors.initials: H
authors.lastname: Yagita
authors.forename: S
authors.initials: S
authors.lastname: Pahwa
mesh_terms: D019138:Antibodies, Blocking / Q000494:pharmacology; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D017209:Apoptosis / Q000276:immunology*; D015704:CD4 Antigens / Q000378:metabolism* / Q000502:physiology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D002469:Cell Separation; D053222:Fas Ligand Protein; D015658:HIV Infections / Q000276:immunology*; D006801:Humans; D008024:Ligands; D008562:Membrane Glycoproteins / Q000096:biosynthesis* / Q000276:immunology / Q000378:metabolism; D009000:Monocytes / Q000276:immunology / Q000378:metabolism* / Q000502:physiology; D012995:Solubility; D019014:fas Receptor / Q000096:biosynthesis* / Q000502:physiology
chemical_list: D019138:Antibodies, Blocking; D000911:Antibodies, Monoclonal; D015704:CD4 Antigens; C505661:FASLG protein, human; D053222:Fas Ligand Protein; D008024:Ligands; D008562:Membrane Glycoproteins; D019014:fas Receptor