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Ligation of the TCR along with the coreceptor CD28 is necessary to elicit T cell activation in vivo, whereas TCR triggering alone does not allow a full T cell response. Upon T cell activation of human peripheral blood T cells, we found that the majority of cAMP was generated in T cell lipid rafts followed by activation of protein kinase A. However, upon TCR and CD28 coligation, beta-arrestin in complex with cAMP-specific phosphodiesterase 4 (PDE4) was recruited to lipid rafts which down-regulated cAMP levels. Whereas inhibition of protein kinase A increased TCR-induced immune responses, inhibition of PDE4 blunted T cell cytokine production. Conversely, overexpression of either PDE4 or beta-arrestin augmented TCR/CD28-stimulated cytokine production. We show here for the first time that the T cell immune response is potentiated by TCR/CD28-mediated recruitment of PDE4 to lipid rafts, which counteracts the local, TCR-induced production of cAMP. The specific recruitment of PDE4 thus serves to abrogate the negative feedback by cAMP which is elicited in the absence of a coreceptor stimulus.

Original publication

DOI

10.4049/jimmunol.173.8.4847

Type

Journal article

Journal

J Immunol

Publication Date

15/10/2004

Volume

173

Pages

4847 - 4858

Keywords

1-Methyl-3-isobutylxanthine, 3',5'-Cyclic-AMP Phosphodiesterases, Arrestins, CD28 Antigens, Cyclic AMP, Cyclic AMP-Dependent Protein Kinases, Cyclic Nucleotide Phosphodiesterases, Type 4, Humans, Lymphocyte Activation, Membrane Microdomains, Receptors, Antigen, T-Cell, Signal Transduction, T-Lymphocytes, beta-Arrestins