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Sensitivity of IL‐5 production to the cAMP‐dependent pathway in human T cells is reduced by exogenous IL‐2 in a phosphoinositide 3‐kinase‐dependent way

The cAMP‐dependent pathway plays an important role in the regulation of T cell‐mediated immune responses by inhibition of T cell proliferation, activation and production of Th1‐like cytokines.Depending on costimulatory signals and on the activation status of T cells, cAMP also regulates the production of Th2‐like cytokines, yet the mechanism is not completely defined. We investigated the effect of costimulation with IL‐2 on cAMP‐mediated inhibition of IL‐5 secretion and the signaling pathways involved in these effects in freshly isolated, α‐CD3/α‐CD28‐stimulated human T lymphocytes. We demonstrate that IL‐2 counteracts the cAMP‐mediated inhibitory effects on IL‐5 secretion by the modulation of phosphoinositide 3‐kinase (PI3‐K)‐dependent signaling. Our results indicate that phosphorylation of cAMP‐responsive element‐binding protein (CREB) and the activity of the small GTPase Rap1 are unlikely involved in the protective effect of IL‐2. Instead, the effect of IL‐2may be mediated by the PI3‐K‐dependent inactivation of the forkhead‐related transcription factor FKHR‐L1, down‐regulation of p27kip and abrogation of the cAMP‐mediated inhibition of activator protein (AP)‐1 binding activity. Together, our results indicate that increased IL‐2‐dependent PI3‐K signaling leads to impaired negative feedback control of the production of Th2‐type cytokine IL‐5 by the cAMP‐dependent pathway.