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Cross-linking of CD4 molecules upregulates Fas antigen expression in
lymphocytes by inducing interferon-gamma and tumor necrosis factor- alpha
secretion
N Oyaizu, TW McCloskey, S Than, R Hu, VS Kalyanaraman and S Pahwa
Department of Pediatrics, North Shore University Hospital-Cornell
University Medical College, Manhasset, NY.
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.
Volume 84,
Issue 8,
pp. 2622-2631,
10/15/1994
Copyright © 1994 by The American Society of Hematology
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