RT Journal Article
SR Electronic
T1 Inhibition of IRF4 in dendritic cells by PRR-independent and -dependent signals inhibit Th2 and promote Th17 responses
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 685008
DO 10.1101/685008
A1 Jihyung Lee
A1 Junyan Zhang
A1 Young-Jun Chung
A1 Jun Hwan Kim
A1 Chae Min Kook
A1 José M. González-Navajas
A1 David S. Herdman
A1 Bernd Nürnberg
A1 Paul A. Insel
A1 Maripat Corr
A1 Ailin Tao
A1 Kei Yasuda
A1 Ian R. Rifkin
A1 David Broide
A1 Roger Sciammas
A1 Nicholas J.G. Webster
A1 Eyal Raz
YR 2019
UL http://biorxiv.org/content/early/2019/06/28/685008.abstract
AB 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.