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

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 Tcells, 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 Tcells is inhibitory of IL-2 production and Tcell proliferation. However, the function and detailed signal transduction mechanisms of the cAMP/PKA pathway in naive T sub(h) cells are less well understood. In this study, we show that calcitonin gene- related peptide (CGRP) down-regulates IL-2 and IFN- gamma production and up- regulates IL-4 production to promote T sub(h)2 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 sub(h)2 cytokine mRNAs were also reproduced by the addition of a cAMP analogue, dibutyryl-cAMP, in CD3/CD28-stimulated naive T sub(h) cells. More interestingly, cAMP/PKA activation in naive T sub(h) cells stimulated with anti- CD3 plus anti-CD28 mAb is essential for inducing IL-4 production and promoting T sub(h)2 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 sub(h)2 polarization by a CD3/CD28 co-stimulation signal and a PKA activating reagent.