1. Inhibition of IRF4 in dendritic cells by PRR-independent and -dependent signals inhibit Th2 and promote Th17 responses.
- Author
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Lee, Jihyung, Zhang, Junyan, Chung, Young-Jun, Kim, Jun Hwan, Kook, Chae Min, González-Navajas, José M, Herdman, David S, Nürnberg, Bernd, Insel, Paul A, Corr, Maripat, Mo, Ji-Hun, Tao, Ailin, Yasuda, Kei, Rifkin, Ian R, Broide, David H, Sciammas, Roger, Webster, Nicholas Jg, and Raz, Eyal
- Subjects
IRF4 ,PRR ,Th17 ,Th2 ,cAMP ,dendritic cells ,immunology ,inflammation ,mouse ,Biochemistry and Cell Biology - Abstract
Cyclic AMP (cAMP) is involved in many biological processes but little is known regarding its role in shaping immunity. Here we show that cAMP-PKA-CREB signaling (a pattern recognition receptor [PRR]-independent mechanism) regulates conventional type-2 Dendritic Cells (cDC2s) in mice and reprograms their Th17-inducing properties via repression of IRF4 and KLF4, transcription factors essential for cDC2-mediated Th2 induction. In mice, genetic loss of IRF4 phenocopies the effects of cAMP on Th17 induction and restoration of IRF4 prevents the cAMP effect. Moreover, curdlan, a PRR-dependent microbial product, activates CREB and represses IRF4 and KLF4, resulting in a pro-Th17 phenotype of cDC2s. These in vitro and in vivo results define a novel signaling pathway by which cDC2s display plasticity and provide a new molecular basis for the classification of novel cDC2 and cDC17 subsets. The findings also reveal that repressing IRF4 and KLF4 pathway can be harnessed for immuno-regulation.
- Published
- 2020