Cyclic AMP differentially modulates CD40L expression on human naïve and memory CD4⁺ T cells

Although differences in naïve and memory T cell signaling have been recognized, how these differences relate to cell regulation and function is not well understood. In this study, we investigated CD40 ligand (CD40L) regulation by cyclic AMP (cAMP) and prostaglandin E₂ (PGE₂) and observed differential effects depending upon the cell subset and mode of activation. cAMP inhibited CD3-induced CD40L in both naïve and memory subsets, although greater inhibition was observed in memory cells. With CD3/CD28 costimulation, cAMP inhibited CD40L in memory cells but had a minimal effect on naïve cells. In primed T cells, cAMP increased CD40L on naïve cells but inhibited expression on memory cells. Differential cAMP effects appear interrelated to calcium signaling since the level of CD40L induced by calcium ionophore was increased by cAMP in both cell subsets, although naïve cells were more calcium responsive. Calcium-dependent calcineurin activity appeared necessary for CD40L expression, although no interaction of calcineurin and cAMP regulation was demonstrable. In contrast, inhibitors of Ca²⁺/calmodulin-dependent protein kinase IV (CaMKIV) blocked cAMP effects to increase CD40L and resulted in marked CD40L inhibition. The importance of CaMKIV in cAMP regulation was confirmed by transfection studies using a dominant negative CaMKIV construct. We conclude that cAMP differentially regulates CD40L expression in a manner that appears dependent upon CaMKIV activation. In view of the central role of CD40L expression in immunity as well as the pathophysiology of common diseases, it is of interest that cAMP can either increase or decrease CD40L expression depending upon the T cell subtype and mechanism of cell activation.