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Phosphodiesterases as Targets for Modulating T-Cell Responses

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Phosphodiesterases as Drug Targets

Part of the book series: Handbook of Experimental Pharmacology ((HEP,volume 204))

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 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.

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Authors and Affiliations

  1. The Biotechnology Centre of Oslo and Centre for Molecular Medicine Norway, Nordic EMBL Partnership, University of Oslo, 1125, Blindern, 0317, Oslo, Norway

    Elisa Bjørgo, Kristine Moltu & Kjetil Taskén

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  1. Elisa Bjørgo
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  2. Kristine Moltu
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  3. Kjetil Taskén
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Correspondence to Kjetil Taskén .

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Editors and Affiliations

  1. School of Medicine, Dept. Molecular Physiology & Biophysics, Vanderbilt University, Light Hall 702, Nashville, 37232-0615, Tennessee, USA

    Sharron H. Francis

  2. HSW 1656, Center for Reproductive Sciences, Parnassus Avenue 513, San Francisco, 94143-0556, California, USA

    Marco Conti

  3. Wolfson Building, University of Glasgow, Glasgow, G12 8QQ, United Kingdom

    Miles D. Houslay

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Bjørgo, E., Moltu, K., Taskén, K. (2011). Phosphodiesterases as Targets for Modulating T-Cell Responses. In: Francis, S., Conti, M., Houslay, M. (eds) Phosphodiesterases as Drug Targets. Handbook of Experimental Pharmacology, vol 204. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-17969-3_15

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