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

• Published in: Proceedings of the National Academy of Sciences - PNAS 2015-02, Vol.112 (5), p.1529-1534
• Main Authors: Lee, Jihyung, Kim, Tae Hoon, Murray, Fiona, Li, Xiangli, Choi, Sara S., Broide, David H., Corr, Maripat, Lee, Jongdae, Webster, Nicholas J. G., Insel, Paul A., Raz, Eyal
• Format: Article
• Language: English
• Subjects: Adoptive Transfer; Animals; Asthma; Asthma - immunology; Binding sites; Biological Sciences; Cells; Chromogranins; Cyclic AMP - metabolism; Dendritic Cells - cytology; Dendritic Cells - metabolism; GTP-Binding Protein alpha Subunits, Gs - genetics; Hypersensitivity - immunology; Mice; Proteins; Rodents; Signal transduction; Th2 Cells - immunology
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1417972112

Significance Allergic asthma is characterized by Th2 type inflammation, leading to airway hyperresponsiveness and remodeling. However, the mechanisms by which DC promote Th2 differentiation remain unclear. Herein we demonstrate that low cAMP levels in DC induce Th2-biased responses in vitro and in vivo. Furthermore, mice with conditional deletion of Gnas in DC ( Gnas ΔCᴰ¹¹ᶜ mice) develop spontaneous bronchial asthma that shares multiple similarities with human asthma. In contrast, increasing cAMP levels inhibit these responses. Thus, regulators of cAMP levels in DC such as G-protein-coupled receptors are non-pattern recognition receptors that play a significant role in CD4 T cell differentiation. 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 Gαs, and Gαi, 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 Gαs in mouse CD11c ⁺ cells ( Gnas ΔCᴰ¹¹ᶜ 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 ΔCᴰ¹¹ᶜ DC affect the Th2 bias. These findings imply that G protein-coupled receptors, the physiological regulators of Gαs and Gαi activation and cAMP formation, act via PKA to regulate Th bias in DC and in turn, Th2-mediated immunopathologies.