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Department of Cellular and Developmental Biology, "La Sapienza" University, Rome, Italy;
Department of Environmental Sciences, Università della Tuscia, Viterbo, Italy; and
Center of Evolutionary Genetics, Consiglio Nazionale delle Ricerche, Rome, Italy
In the present study, we have aimed at clarifying the CD4-dependent
molecular mechanisms that regulate human memory T cell susceptibility
to both Fas (CD95)-dependent and Bcl-2-dependent apoptotic pathways
following antigenic challenge. To address this issue, we used an
experimental system of viral and alloantigen-specific T cell lines and
clones and two ligands of CD4 molecules, Leu-3a mAb and HIV gp120. We
demonstrate that CD4 engagement before TCR triggering suppresses the
TCR-mediated neosynthesis of the Flice-like inhibitory protein and
transforms memory T cells from a CD95-resistant to a CD95-susceptible
phenotype. Moreover, evidence that the apoptotic programs were executed
while Fas ligand mRNA expression was inhibited led us to analyze
Bcl-2-dependent pathways. The data show that the engagement of CD4
separately from TCR influences the expression of the proapoptotic
protein Bax independently of the anti-apoptotic protein Bcl-2,
whereas Ag activation coordinately modulates both Bax and Bcl-2. The
increased expression of Bax and the consequent dissipation of the
mitochondrial transmembrane potential (
m) suggest a
novel immunoregulatory function of CD4 and demonstrate that both
passive cell death and activation-induced cell death are operative in
CD4+ memory T cells. Furthermore, analysis of the
mechanisms by which IL-2 and IL-4 cytokines exert their protective
function on CD4+ T cells in the presence of soluble CD4
ligands shows that they were able to revert susceptibility to
Bax-mediated but not to CD95-dependent apoptotic
pathways.
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