Phosphodiesterases as targets for modulating T-cell responses.

The cAMP-protein kinase A (PKA) signaling pathway is strongly involved in the regulation and modulation of immune responses, and cAMP is the most potent and acute inhibitor of T-cell activation. Thus, cAMP levels in the cell must be tightly regulated. Cyclic AMP-specific phosphodiesterases (PDEs) provide the only mechanism for degrading cAMP in cells, thereby functioning as key regulators of signaling. To obtain a complete immune response with optimal cytokine production and T-cell proliferation, ligation of both the T-cell receptor (TCR) and the CD28 receptor is required. However, engagement of the TCR in primary T cells is followed by rapid cAMP production in lipid rafts and activation of the cAMP- PKA-Csk pathway inhibiting proximal T-cell signaling. In contrast, TCR/CD28 costimulation leads to the recruitment of a PDE4/β-arrestin complex to rafts in a phosphatidylinositol 3-kinase (PI3K)-dependent manner, resulting in the downregulation of cAMP levels. Thus, the activities of both PKA and PDE4 seem to be important for regulation of TCR-induced signaling and T-cell function. The use of selective inhibitors has revealed that PDEs are important drug targets in several diseases with an inflammatory component where immune function is important such as asthma, chronic obstructive pulmonary disease (COPD), cardiovascular diseases, and neurological disorders. PDEs are also interesting drug targets in immunosuppression following transplantation and for modulation of immune responses.