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

• Published in: eLife Vol. 9
• Main Authors: 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
• Format: Journal Article
• Language: English
• Published: England eLife Sciences Publications Ltd 04-02-2020; eLife Sciences Publications, Ltd
• Subjects: AMP; Animals; Antigens; Bias; cAMP; Cdc2 protein; Cell Line, Tumor; Cholera; Cyclic AMP - immunology; Cyclic AMP - metabolism; Cyclic AMP response element-binding protein; Cytokines; Dendritic cells; Dendritic Cells - immunology; Dendritic Cells - metabolism; Gene expression; Genotype & phenotype; Helper cells; Humans; Immunology and Inflammation; Interferon regulatory factor 4; Interferon Regulatory Factors - antagonists & inhibitors; Interferon Regulatory Factors - immunology; Interferon Regulatory Factors - metabolism; IRF4; KLF4 protein; Kruppel-Like Factor 4; Lymphocytes; Lymphocytes T; Mice; Pattern recognition receptors; Phenotypes; Protein kinase A; PRR; Receptors, Pattern Recognition - immunology; Receptors, Pattern Recognition - metabolism; Signal transduction; Signal Transduction - immunology; Th17; Th17 Cells - immunology; Th17 Cells - metabolism; Th2; Th2 Cells - immunology; Th2 Cells - metabolism; Transcription factors; PRR; mouse; dendritic cells; IRF4; inflammation; cAMP; Th17; immunology; Th2
• ISSN: 2050-084X; 2050-084X
• DOI: 10.7554/eLife.49416

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.