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.
The study was funded by NIH Grants HD12303, CA23100, and DK063491 (to N.J.G.W.); NIH Grants AI 38425, AI 70535, and AI 72115 (to D.B.); NIH Grants AI095623 and AI077989 (to E.R.); Veterans Affairs Grant I01BX000130 (to N.J.G.W.); and a grant from the Crohn’s and Colitis Foundation of America (to E.R.).
- Adoptive Transfer
- Cyclic AMP
- Dendritic Cells
- GTP-Binding Protein alpha Subunits, Gs
- Th2 Cells
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- School of Medicine, Medical Sciences & Nutrition, Cardiometabolic Disease
- School of Medicine, Medical Sciences & Nutrition, Aberdeen Cardiovascular and Diabetes Centre
- School of Medicine, Medical Sciences & Nutrition, Medical Sciences - Senior Lecturer
- School of Medicine, Medical Sciences & Nutrition, Institute of Medical Sciences