CROSS-LINKING OF CD4 MOLECULES UP-REGULATES FAS ANTIGEN EXPRESSION INLYMPHOCYTES BY INDUCING INTERFERON-GAMMA AND TUMOR-NECROSIS-FACTOR-ALPHA SECRETION

We have recently shown that, in unfractioned peripheral blood mononucl ear cells (PBMCs), the cross-linking of CD4 molecules (CD4XL) is suffi cient to induce T-cell apoptosis. However, the underlying mechanism fo r the CD4XL-mediated T-cell apoptosis is largely unknown. Several rece nt studies have shown that Fas antigen (Ag), a cell-surface molecule, mediates apoptosis-triggering signals. We show here that cross-linking of CD4 molecules, induced either by anti-CD4 monoclonal antibody (MoA b) Leu3a or by human immunodeficiency virus-1 (HIV-1) envelope protein gp160, upregulates Fas Ag expression as well as Fas mRNA in normal ly mphocytes. Addition of the tyrosine protein kinase inhibitor genistein or of the immunosuppressive agent cyclosporin A abrogated these effec ts. The upregulation of Fas Ag closely correlated with apoptotic cell death, as determined by flow cytometry. In addition, CD4XL resulted in the induction of interferon-gamma (INF-gamma) and tumor necrosis fact or-alpha (TNF-alpha) in the absence of interleukin-2 (IL-2) and IL-4 s ecretion in PBMCs. Both INF-gamma and TNF-alpha were found to contribu te to Fas Ag upregulation and both anti-INF-gamma and anti-TNF-alpha a ntibodies blocked CD4XL-induced Fas Ag upregulation and lymphocyte apo ptosis. These findings strongly suggest that aberrant cytokine secreti on induced by CD4XL and consequent upregulation of Fas Ag expression m ight play a critical role in triggering peripheral T-cell apoptosis an d thereby contribute to HIV disease pathogenesis. (C) 1994 by The Amer ican Society of Hematology.