Inhibition of IRF4 in dendritic cells by PRR-independent and -dependent signals inhibit Th2 and promote Th17 responses
Abstrak
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.
Topik & Kata Kunci
Penulis (18)
Jihyung Lee
Junyan Zhang
Young-Jun Chung
Jun Hwan Kim
Chae Min Kook
José M González-Navajas
David S Herdman
Bernd Nürnberg
Paul A Insel
Maripat Corr
Ji-Hun Mo
Ailin Tao
Kei Yasuda
Ian R Rifkin
David H Broide
Roger Sciammas
Nicholas JG Webster
Eyal Raz
Akses Cepat
- Tahun Terbit
- 2020
- Sumber Database
- DOAJ
- DOI
- 10.7554/eLife.49416
- Akses
- Open Access ✓