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

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 T_h 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 T_h2 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 T_h2 cytokine mRNAs were also reproduced by the addition of a cAMP analogue, dibutyryl‐cAMP, in CD3/CD28‐stimulated naive T_h cells. More interestingly, cAMP/PKA activation in naive T_h cells stimulated with anti‐CD3 plus anti‐CD28 mAb is essential for inducing IL‐4 production and promoting T_h2 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 T_h2 polarization by a CD3/CD28 co‐stimulation signal and a PKA activating reagent.