TCR- and CD28-mediated recruitment of phosphodiesterase 4 to lipid rafts potentiates TCR signaling.
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.
Biotechnology Centre, University of Oslo, Norway.
Hilde
H
Abrahamsen
George
G
Baillie
Jacob
J
Ngai
Torkel
T
Vang
Konstantina
K
Nika
Anja
A
Ruppelt
Tomas
T
Mustelin
Manuela
M
Zaccolo
Miles
M
Houslay
Kjetil
K
Taskén
D015056:1-Methyl-3-isobutylxanthine / Q000494:pharmacology; D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000502:physiology*; D019390:Arrestins / Q000378:metabolism; D018106:CD28 Antigens / Q000502:physiology*; D000242:Cyclic AMP / Q000096:biosynthesis; D017868:Cyclic AMP-Dependent Protein Kinases / Q000502:physiology; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D006801:Humans; D008213:Lymphocyte Activation; D021962:Membrane Microdomains / Q000201:enzymology*; D011948:Receptors, Antigen, T-Cell / Q000502:physiology*; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000276:immunology; D000071557:beta-Arrestins
D019390:Arrestins; D018106:CD28 Antigens; D011948:Receptors, Antigen, T-Cell; D000071557:beta-Arrestins; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; D015105:3',5'-Cyclic-AMP Phosphodiesterases; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D015056:1-Methyl-3-isobutylxanthine