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

Abstract

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.

ACKNOWLEDGMENTS

We thank Gregory J. Kato and Donald H. Maurice for helpful comments on the manuscript. We also thank the members of the Madrenas laboratory (in particular Kristi A. McConnell, Peter J. Darlington, and John Johnson) for fruitful discussions on PDEs.

This work was supported by grants from the Canadian Institutes of Health Research (CIHR), the Kidney Foundation of Canada, and the Multi-Organ Transplant Program of the London Health Sciences Centre. MG.K. is the recipient of a CIHR M.D./Ph.D. studentship, and J.M. holds a Canada Research Chair in Transplantation and Immunobiology.