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Molecular and Cellular Biology, November 2003, p. 8042-8057, Vol. 23, No. 22
0270-7306/03/$08.00+0     DOI: 10.1128/MCB.23.22.8042-8057.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Regulation of T-Cell Activation by Phosphodiesterase 4B2 Requires Its Dynamic Redistribution during Immunological Synapse Formation

Jacqueline Arp,1,2 Mark G. Kirchhof,1,2 Miren L. Baroja,1,2 Steven H. Nazarian,1,2 Thu A. Chau,1,2 Craig A. Strathdee,1,{dagger} Eric H. Ball,3 and Joaquín Madrenas1,2*

Robarts Research Institute,1 Department of Microbiology and Immunology and Department of Medicine,2 Department of Biochemistry, The University of Western Ontario, London, Ontario, Canada N6A 5K83

Received 31 March 2003/ Returned for modification 14 May 2003/ Accepted 11 August 2003

Stimulation of T cells through their antigen receptors (TCRs) causes a transient increase in the intracellular concentration of cyclic AMP (cAMP). However, sustained high levels of cAMP inhibit T-cell responses, suggesting that TCR signaling is coordinated with the activation of cyclic nucleotide phosphodiesterases (PDEs). The molecular basis of such a pathway is unknown. Here we show that TCR-dependent signaling activates PDE4B2 and that this enhances interleukin-2 production. Such an effect requires the regulatory N terminus of PDE4B2 and correlates with partitioning within lipid rafts, early targeting of this PDE to the immunological synapse, and subsequent accumulation in the antipodal pole of the T cell as activation proceeds.

* Corresponding author. Mailing address: Robarts Research Institute, P.O. Box 5015, London, Ontario, Canada N6A 5K8. Phone: (519) 663-5777, ext. 34242. Fax: (519) 663-3789. E-mail: madrenas{at}robarts.ca.

{dagger} Present address: Amgen Inc., Seattle, WA 98101.

Molecular and Cellular Biology, November 2003, p. 8042-8057, Vol. 23, No. 22
0022-538X/03/$08.00+0     DOI: 10.1128/MCB.23.22.8042-8057.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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