Overview of the Inhibitory Effects of cAMP on T-Cell Biology
A variety of molecules, including cAMP analogs, direct AC activators (e.g., forskolin and cholera toxin) and PDE inhibitors have been used to elucidate the diverse effects of intracellular cAMP accumulation on T-cell biology. In the presence of such molecules (223–228) as well as by A2AR triggering (125, 126, 229) the capacity of previously unstimulated T cells, CD4+ or unfractionated, to differentiate post-activation toward cells that produce Th1 (125, 126, 223–225, 229) or Th2 (226–229)-signature cytokines is drastically diminished. This occurs in a PKA-dependent fashion (230, 231) through multi-level disruption of TCR- or CD28-induced signaling (122, 232). Intriguingly, A2AR agonist-induced impairment of IFNγ production remains evident even when A2AR agonist-pretreated T cells are re-stimulated in the absence of this agent (139). Furthermore, agents that directly activate the cAMP pathway (233–235), as well as adenosine (122, 138, 232, 236, 237), have been shown to restrict stimulation-induced AKT activation (122, 232, 233, 238) and to induce stabilization of β-catenin, which restricts maturation toward terminally differentiated effector cells (239). Moreover, such agents can prevent FasL upregulation, thus averting FasL-mediated activation-induced cell death (AICD) (127, 138, 235, 237). Finally, such molecules abolish mitogenic-stimulus-induced T cell proliferation, in a PKA-dependent manner (240), by downmodulating the transmission of TCR/ CD28- and IL-2 (241)-initiated signaling, as well as IL-2 production (126, 229, 231) and IL-2Ra expression (242).
Forskolin, cAMP analogs, PDE inhibitors (152, 243–245) and adenosine (188, 246–248) also diminish T cell adherence (152, 243, 246, 248) by down-modulating the expression levels of ICAM-1 (249, 250) as well as of the integrins α4 (251, 252) and β2 (251, 253), components of VLA-4 and LFA-1, respectively. Such agents also impair T-cell migration (188, 244, 245, 247) by inducing KCa3.1 inhibition (188, 189). In addition, cAMP-mediated signaling (230, 254, 255) or the presence of A2AR agonists (139, 168, 230, 231) diminishes T cell cytotoxicity, in a PKA-dependent manner (168, 230, 231), probably as a result of impaired TCR signaling, motility/adhesion, granule exocytosis (138), as well as due to decreased expression of FasL, Granzyme B (GzB), and perforin (127).
Lastly, cholera toxin (256), PDE inhibitors (257–259), forskolin (157) and A2AR agonists (126, 260) not only skew T cells toward the Treg lineage via induction of FoxP3 expression (126, 256–258, 260), but also enhance the capacity of Treg cells to suppress responder T cells (258–260), at least in part by upregulating CTLA-4 levels (157, 260). Thus, cAMP can potently diminish the differentiation and effector activities of CD4+ and CD8+ T cells, while promoting the differentiation toward Tregs, as well as their suppressive capacity.