Inhibition of IRF4 in dendritic cells by PRR-independent and -dependent signals inhibit Th2 and promote Th17 responses
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
Affiliations
Jihyung Lee
Department of Medicine, University of California San Diego, San Diego, United States
Junyan Zhang
Department of Medicine, University of California San Diego, San Diego, United States; The Second Affiliated Hospital of Guangzhou Medical University (GMU), The State Key Laboratory of Respiratory Disease, Guangdong Provincial Key Laboratory of Allergy & Clinical Immunology, Guangzhou, China; Center for Immunology, Inflammation and Immune-mediated disease, GMU, Guangzhou, China
Young-Jun Chung
Department of Medicine, University of California San Diego, San Diego, United States; Department of Otorhinolaryngology-Head and Neck Surgery, Dankook University College of Medicine, Chungnam, Republic of Korea
Jun Hwan Kim
Department of Medicine, University of California San Diego, San Diego, United States
Chae Min Kook
Department of Medicine, University of California San Diego, San Diego, United States
José M González-Navajas
Center for Immunology, Inflammation and Immune-mediated disease, GMU, Guangzhou, China; Alicante Institute for Health and Biomedical Research (ISABIAL - FISABIO), Alicante, Spain; Networked Biomedical Research Center for Hepatic and Digestive Diseases (CIBERehd), Institute of Health Carlos III, Madrid, Spain
David S Herdman
Department of Medicine, University of California San Diego, San Diego, United States
Department of Pharmacology and Experimental Therapy, University of Tübingen, Tübingen, Germany
Paul A Insel
Department of Medicine, University of California San Diego, San Diego, United States; Department of Pharmacology, University of California San Diego, San Diego, United States
Maripat Corr
Department of Medicine, University of California San Diego, San Diego, United States
Ji-Hun Mo
Department of Otorhinolaryngology-Head and Neck Surgery, Dankook University College of Medicine, Chungnam, Republic of Korea
Ailin Tao
The Second Affiliated Hospital of Guangzhou Medical University (GMU), The State Key Laboratory of Respiratory Disease, Guangdong Provincial Key Laboratory of Allergy & Clinical Immunology, Guangzhou, China; Center for Immunology, Inflammation and Immune-mediated disease, GMU, Guangzhou, China
Kei Yasuda
Boston University School of Medicine, Boston, United States
Ian R Rifkin
Boston University School of Medicine, Boston, United States; VA Boston Healthcare System, Boston, United States
David H Broide
Department of Medicine, University of California San Diego, San Diego, United States
Roger Sciammas
Center for Comparative Medicine, University of California, Davis, Davis, United States
Nicholas JG Webster
Department of Medicine, University of California San Diego, San Diego, United States; VA San Diego Healthcare System, San Diego, United States
Department of Medicine, University of California San Diego, San Diego, United States; Center for Immunology, Inflammation and Immune-mediated disease, GMU, Guangzhou, China
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.
