Up-regulation of IL-4 production by the activated cAMP/cAMP-dependent protein kinase (protein kinase A) pathway in CD3/CD28-stimulated naive T cells

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Abstract
The signal transduction of the cAMP/cAMP‐dependent protein kinase [protein kinase A (PKA)] pathway through multiple receptors is critical for many processes in all cell types. In T cells, the engagement of both the TCR–CD3 complex and the CD28 co‐stimulatory molecule also induces cAMP, and subsequently activates PKA. It is believed that elevation of cAMP levels in T cells is inhibitory of IL‐2 production and T cell proliferation. However, the function and detailed signal transduction mechanisms of the cAMP/PKA pathway in naive Th cells are less well understood. In this study, we show that calcitonin gene‐related peptide (CGRP) down‐regulates IL‐2 and IFN‐γ production and up‐regulates IL‐4 production to promote Th2 differentiation by moderate activation of the cAMP/PKA pathway via the CGRP receptor in the presence of a CD3/CD28 co‐stimulation signal. The IL‐4 production and transcriptional activation of Th2 cytokine mRNAs were also reproduced by the addition of a cAMP analogue, dibutyryl‐cAMP, in CD3/CD28‐stimulated naive Th cells. More interestingly, cAMP/PKA activation in naive Th cells stimulated with anti‐CD3 plus anti‐CD28 mAb is essential for inducing IL‐4 production and promoting Th2 differentiation; in addition, NF‐AT is a downstream effector of the cAMP/PKA signaling pathway. These findings indicate that the cAMP/PKA pathway transduces the critical activation signal to Th2 polarization by a CD3/CD28 co‐stimulation signal and a PKA activating reagent.