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Inhibition of IRF4 in dendritic cells by PRR-independent and -dependent signals inhibit Th2 and promote Th17 responses.

  • Author(s): 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
  • Raz, Eyal
  • et al.
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.

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