Citation

Cyclic AMP (cAMP) is involved in multiple biological processes. However, little is known about its role in shaping immunity. Here we show that cAMP-PKA-CREB signaling (a pattern recognition receptor [PRR]-independent) regulates conventional type-2 Dendritic Cells (cDC2s), but not cDC1s and reprograms their Th17-inducing properties via repression of IRF4 and KLF4, transcription factors (TFs) for Th2 induction. Genetic loss of IRF4 phenocopies the effects of cAMP signaling on Th17-induction, indicating that the cAMP effect is secondary to repression of IRF4. Moreover, signaling in cDC2s by a PRR-dependent microbial product, curdlan, represses IRF4 and KLF4, resulting in a pro-Th17 phenotype. These results define a novel signaling pathway by which cDC2s display plasticity and provide a new molecular basis for the novel cDC2 and cDC17 classification. In addition, the data reveal that cAMP signaling can alter DCs function and fate by repressing IRF4 and KLF4, a pathway that can be harnessed for immuno-regulation.