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* Laboratory of Bacteriology and Medical Micology, Istituto Superiore di Sanità, Rome, Italy;
Laboratory of Immunology and Unesco Center, Istituto Nazionale Malattie Infettive "L. Spallanzani" Hospital, Rome, Italy; and
Section of Toxicology and Biomedicine, Ente Nazionale Energie Alternative, Casaccia, Rome, Italy
The CTLA-4 (CD152) molecule is up-regulated upon T cell activation
and proliferation, and plays a critical role in the inhibition of
immune responses. We show in this study that cAMP induces up-regulation
of CD152 in human CD4+ T lymphocytes. This effect occurs in
the absence of the up-regulation of CD69 and CD25 activation markers
and T cell proliferation. In addition, we found that the
Ca2+ ionophore ionomycin also up-regulates CD152, and that
the combination of a cAMP analog or cAMP inducers with ionomycin
further enhances the expression of CD152 in resting CD4+ T
lymphocytes. However, cyclosporin A, which inhibits
Ca2+/calcineurin signaling pathway, fully prevented the
ionomycin- but not the cAMP-induced up-regulation of CD152. The effects
of cAMP and ionomycin involve increase of both CD152 mRNA transcripts,
coding for the membrane and the soluble forms of CD152. Furthermore, we
show that CD152 molecules are translocated to the membrane and are
functional, as their engagement by specific mAbs prevented NF-
B
activation by anti-CD3/CD28 stimulation. These findings demonstrate
that at least two novel signal pathways regulate CTLA-4 gene expression
and CD152 molecule up-regulation in human CD4+ T
lymphocytes, in the absence of full T cell
activation.
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