Cyclic AMP concentrations in dendritic cells induce and regulate Th2 immunity and allergic asthma

The inductive role of dendritic cells (DC) in Th2 differentiation has not been fully defined. We addressed this gap in knowledge by focusing on signaling events mediated by the heterotrimeric GTP binding proteins G alpha s, and G alpha i, which respectively stimulate and inhibit the activation of adenylyl cyclases and the synthesis of cAMP. We show here that deletion of Gnas, the gene that encodes Gas in mouse CD11c(+) cells (Gnas(Delta CD11c) mice), and the accompanying decrease in cAMP provoke Th2 polarization and yields a prominent allergic phenotype, whereas increases in cAMP inhibit these responses. The effects of cAMP on DC can be demonstrated in vitro and in vivo and are mediated via PKA. Certain gene products made by Gnas(Delta CD11c) DC affect the Th2 bias. These findings imply that G protein-coupled receptors, the physiological regulators of Gas and Gai activation and cAMP formation, act via PKA to regulate Th bias in DC and in turn, Th2-mediated immunopathologies.