Biology Reference
In-Depth Information
Phosphodiesterases as Targets for Modulating
T-Cell Responses
Elisa Bjørgo, Kristine Moltu, and Kjetil Task´n
Contents
1 Regulation of cAMP Levels in T Cells . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 346
1.1 The cAMP-PKA-Csk Inhibitory Pathway Modulates
T-Cell Immune Function . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 348
1.2 PDEs Are Key Regulatory Players in Modulating T-Cell Immune Responses . . . . . 349
1.3 TCR-Induced cAMP Production in T-Cell Lipid Rafts . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 350
1.4 The Functional Role of PDE7 in T Cells . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 356
2 Concluding Remarks . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 356
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 357
Abstract 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 produc-
tion 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/
b
-arrestin complex to rafts in a
phosphatidylinositol 3-kinase (PI3K)-dependent manner, resulting in the down-
regulation 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
E. Bjørgo, K. Moltu, and K. Task
´
n(
*
)
The Biotechnology Centre of Oslo and Centre for Molecular Medicine Norway, Nordic EMBL
Partnership, University of Oslo, P.O. Box 1125, Blindern 0317, Oslo, Norway
e-mail: kjetil.tasken@biotek.uio.no
