Cross-linking of CD4 molecules upregulates Fas antigen expression in lymphocytes by inducing interferon-gamma and tumor necrosis factor-alpha secretion.
We have recently shown that, in unfractioned peripheral blood mononuclear cells (PBMCs), the cross-linking of CD4 molecules (CD4XL) is sufficient to induce T-cell apoptosis. However, the underlying mechanism for the CD4XL-mediated T-cell apoptosis is largely unknown. Several recent 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 (MoAb) Leu3a or by human immunodeficiency virus-1 (HIV-1) envelope protein gp160, upregulates Fas Ag expression as well as Fas mRNA in normal lymphocytes. Addition of the tyrosine protein kinase inhibitor genistein or of the immunosuppressive agent cyclosporin A abrogated these effects. 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 (IFN-gamma) and tumor necrosis factor-alpha (TNF-alpha) in the absence of interleukin-2 (IL-2) and IL-4 secretion in PBMCs. Both INF-gamma and TNF-alpha were found to contribute to Fas Ag upregulation and both anti-IFN-gamma and anti-TNF-alpha antibodies blocked CD4XL-induced Fas Ag upregulation and lymphocyte apoptosis. These findings strongly suggest that aberrant cytokine secretion induced by CD4XL and consequent upregulation of Fas Ag expression might play a critical role in triggering peripheral T-cell apoptosis and thereby contribute to HIV disease pathogenesis.
Oyaizu
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N
Department of Pediatrics, North Shore University Hospital-Cornell University Medical College, Manhasset, NY.
McCloskey
T W
TW
Than
S
S
Hu
R
R
Kalyanaraman
V S
VS
Pahwa
S
S
D000906:Antibodies / Q000494:pharmacology; D000914:Antibodies, Viral / Q000494:pharmacology; D000954:Antigens, Surface / Q000235:genetics*; D017209:Apoptosis; D015704:CD4 Antigens / Q000737:chemistry / Q000502:physiology*; D003432:Cross-Linking Reagents; D016572:Cyclosporine / Q000494:pharmacology; D005455:Fluorescent Antibody Technique; D005786:Gene Expression Regulation; D015686:Gene Products, env / Q000494:pharmacology; D019833:Genistein; D015699:HIV Envelope Protein gp120 / Q000276:immunology; D019302:HIV Envelope Protein gp160; D015497:HIV-1; D006801:Humans; D007371:Interferon-gamma / Q000276:immunology / Q000378:metabolism* / Q000494:pharmacology; D007529:Isoflavones / Q000494:pharmacology; D011498:Protein Precursors / Q000494:pharmacology; D012333:RNA, Messenger / Q000096:biosynthesis; D013601:T-Lymphocytes / Q000276:immunology*; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology / Q000378:metabolism* / Q000494:pharmacology; D019014:fas Receptor
D000906:Antibodies; D000914:Antibodies, Viral; D000954:Antigens, Surface; D015704:CD4 Antigens; D003432:Cross-Linking Reagents; D015686:Gene Products, env; D015699:HIV Envelope Protein gp120; D019302:HIV Envelope Protein gp160; D007529:Isoflavones; D011498:Protein Precursors; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D019014:fas Receptor; D007371:Interferon-gamma; D016572:Cyclosporine; D019833:Genistein