Increased cyclic adenosine monophosphate levels block progression but not initiation of human T cell proliferation

The involvement of cyclic nucleotides in the regulation of cell growth is well established as are the findings that sustained high levels of intracellular cyclic adenosine monophosphate (cAMP) inhibit ligand-induced lymphocyte proliferation. However, there is considerable controversy concerning the precise role of cAMP in this regard or the target of its action. A number of studies with cAMP analogs or forskolin have implicated the early events after ligand binding as being particularly susceptible whereas others have failed to do so or offered alternate targets. We have examined the effects of cell permeant analogs of cAMP and forskolin on human T cell proliferation. After brief exposure to submitogenic concentrations of PHA or phorbol ester plus ionomycin, we have examined the effects of increased cAMP levels during initial activation (or induction of competence) and progression to DNA synthesis. We find that these drugs that inhibit T cell proliferation have little effect on induction of competence or early activation events including transmembrane Ca2+ uptake, release of Ca2+ from internal stores or induction of the genes encoding c-fos or early growth response gene. In contrast, it is the progression phase of the proliferative response which appears to be the major target for cAMP-protein kinase A-mediated inhibition of human T cell proliferation.