Cross-linking of CD4 molecules upregulates Fas antigen expression in lymphocytes by inducing interferon-γ and tumor necrosis factor-α secretion

Naoki Oyaizu, Thomas W. McCloskey, Soe Than, Rong Hu, Vaniambadi S. Kalyanaraman, Savita G Pahwa

Research output: Contribution to journalArticle

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Abstract

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-γ (INF-γ) and tumor necrosis factor-α (TNF-α) in the absence of interleukin-2 (IL-2) and IL-4 secretion in PBMCs. Both INF-γ and TNF-α were found to contribute to Fas Ag upregulation and both anti-INF-γ and anti-TNF-α 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.

Original languageEnglish
Pages (from-to)2622-2631
Number of pages10
JournalBlood
Volume84
Issue number8
StatePublished - Oct 15 1994
Externally publishedYes

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CD95 Antigens
CD4 Antigens
Lymphocytes
Interferons
Up-Regulation
Tumor Necrosis Factor-alpha
T-cells
Apoptosis
T-Lymphocytes
Blood Cells
Human Immunodeficiency Virus env Gene Products
Blood
Flow cytometry
Genistein
Cell death
Protein Kinase Inhibitors
Immunosuppressive Agents
Viruses
Interleukin-4
Protein-Tyrosine Kinases

ASJC Scopus subject areas

  • Hematology

Cite this

Cross-linking of CD4 molecules upregulates Fas antigen expression in lymphocytes by inducing interferon-γ and tumor necrosis factor-α secretion. / Oyaizu, Naoki; McCloskey, Thomas W.; Than, Soe; Hu, Rong; Kalyanaraman, Vaniambadi S.; Pahwa, Savita G.

In: Blood, Vol. 84, No. 8, 15.10.1994, p. 2622-2631.

Research output: Contribution to journalArticle

Oyaizu, Naoki ; McCloskey, Thomas W. ; Than, Soe ; Hu, Rong ; Kalyanaraman, Vaniambadi S. ; Pahwa, Savita G. / Cross-linking of CD4 molecules upregulates Fas antigen expression in lymphocytes by inducing interferon-γ and tumor necrosis factor-α secretion. In: Blood. 1994 ; Vol. 84, No. 8. pp. 2622-2631.
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