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 language | English |
|---|---|
| Pages (from-to) | 2622-2631 |
| Number of pages | 10 |
| Journal | Blood |
| Volume | 84 |
| Issue number | 8 |
| State | Published - Oct 15 1994 |
| Externally published | Yes |
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ASJC Scopus subject areas
- Hematology
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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 journal › Article
}
TY - JOUR
T1 - Cross-linking of CD4 molecules upregulates Fas antigen expression in lymphocytes by inducing interferon-γ and tumor necrosis factor-α secretion
AU - Oyaizu, Naoki
AU - McCloskey, Thomas W.
AU - Than, Soe
AU - Hu, Rong
AU - Kalyanaraman, Vaniambadi S.
AU - Pahwa, Savita G
PY - 1994/10/15
Y1 - 1994/10/15
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=0027960659&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=0027960659&partnerID=8YFLogxK
M3 - Article
C2 - 7522637
AN - SCOPUS:0027960659
VL - 84
SP - 2622
EP - 2631
JO - Blood
JF - Blood
SN - 0006-4971
IS - 8
ER -