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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
eLife | 2020

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.

Pubmed ID: 32014112

Associated grants

  • Agency: NIDDK NIH HHS, United States
    Id: T32 DK007044
  • Agency: NCI NIH HHS, United States
    Id: CA196853
  • Agency: NIDDK NIH HHS, United States
    Id: DK063491
  • Agency: NCI NIH HHS, United States
    Id: CA023100
  • Agency: NIAID NIH HHS, United States
    Id: U01 AI125860
  • Agency: NHLBI NIH HHS, United States
    Id: R01 HL141999
  • Agency: NIAID NIH HHS, United States
    Id: R01 AI113145
  • Agency: NHLBI NIH HHS, United States
    Id: HL141999
  • Agency: NHLBI NIH HHS, United States
    Id: HL141999a
  • Agency: BLRD VA, United States
    Id: IK6 BX005224
  • Agency: NCI NIH HHS, United States
    Id: P30 CA023100

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Global nonprofit biological resource center (BRC) and research organization that provides biological products, technical services and educational programs to private industry, government and academic organizations. Its mission is to acquire, authenticate, preserve, develop and distribute biological materials, information, technology, intellectual property and standards for the advancement and application of scientific knowledge. The primary purpose of ATCC is to use its resources and experience as a BRC to become the world leader in standard biological reference materials management, intellectual property resource management and translational research as applied to biomaterial development, standardization and certification. ATCC characterizes cell lines, bacteria, viruses, fungi and protozoa, as well as develops and evaluates assays and techniques for validating research resources and preserving and distributing biological materials to the public and private sector research communities.

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RRID:SCR_008520

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RRID:SCR_008988

American chemical, life science and biotechnology company owned by Merck KGaA. Merger of Sigma Chemical Company and Aldrich Chemical Company. Provides organic and inorganic chemicals, building blocks, reagents, advanced materials and stable isotopes for chemical synthesis, medicinal chemistry and materials science, antibiotics, buffers, carbohydrates, enzymes, forensic tools, hematology and histology, nucleotides, proteins, peptides, amino acids and their derivatives.

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RRID:SCR_010881

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RRID:SCR_014583

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RRID:SCR_015687

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RRID:SCR_017148

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