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Specific CD3 Association of a Phosphodiesterase 4B Isoform Determines Its Selective Tyrosine Phosphorylation After CD3 Ligation¹

Miren L. Baroja^*, Lenora B. Cieslinski, Theodore J. Torphy, Ronald L. Wange^§ and Joaquín Madrenas^2,*,

^* Transplantation and Immunobiology Group, John P. Robarts Research Institute, and Departments of Microbiology and Immunology, and Medicine, University of Western Ontario, London, Ontario, Canada; Division of Pharmacological Sciences, SmithKline Beecham Pharmaceuticals, King of Prussia, PA 19406; and ^§ Gerontology Research Center, National Institute on Aging, National Institutes of Health, Baltimore, MD 21224

cAMP-specific phosphodiesterases (PDE) comprise an extensive family of enzymes that control intracellular levels of cAMP and thus regulate T cell responses. It is not known how the function of these enzymes is altered by TCR engagement. We have examined this issue by studying one of the PDE isozymes (PDE4B). PDE4B RNA and protein were detected in resting PBLs, and the levels of PDE4B protein increased with cell cycling. In peripheral blood T cells, two previously reported PDE4B isoforms could be detected: one was 75–80 kDa (PDE4B1) and the other was 65–67 kDa (PDE4B2). These two isoforms differed in their N-terminal sequence, with the presence of four potential myristylation sites in the PDE4B2 that are absent in PDE4B1. Consequently, only PDE4B2 was found in association with the CD3 chain of the TCR. In addition, although both isoforms were phosphorylated in tyrosines in pervanadate-stimulated T cells, only the TCR-associated PDE4B2 was tyrosine-phosphorylated following CD3 ligation. The kinetics of phosphorylation of TCR-associated PDE4B2 correlated with changes in cAMP levels, suggesting that tyrosine phosphorylation of the TCR-associated PDE4B isoform upon engagement of this receptor may be an important regulatory step in PDE4B function. Our results reveal that selectivity of PDE4B activation can be achieved by differential receptor association and phosphorylation of the alternatively spliced forms of this PDE.

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