Transcriptional repression of ifn regulatory factor 7 by myc is critical for type i ifn production in human plasmacytoid dendritic cells

Tae Whan Kim, Seunghee Hong, Yin Lin, Elise Murat, Hyemee Joo, Taeil Kim, Virginia Pascual, Yong Jun Liu

Research output: Contribution to journalArticle

16 Scopus citations

Abstract

Type I IFNs are crucial mediators of human innate and adaptive immunity and are massively produced from plasmacytoid dendritic cells (pDCs). IFN regulatory factor (IRF)7 is a critical regulator of type I IFN production when pathogens are detected by TLR 7/9 in pDC. However, hyperactivation of pDC can cause life-threatening autoimmune diseases. To avoid the deleterious effects of aberrant pDC activation, tight regulation of IRF7 is required. Nonetheless, the detailed mechanisms of how IRF7 transcription is regulated in pDC are still elusive. MYC is a well-known highly pleiotropic transcription factor; however, the role of MYC in pDC function is not well defined yet. To identify the role of transcription factor MYC in human pDC, we employed a knockdown technique using human pDC cell line, GEN2.2. When we knocked down MYC in the pDC cell line, production of IFN-stimulated genes was dramatically increased and was further enhanced by the TLR9 agonist CpGB. Interestingly, MYC is shown to be recruited to the IRF7 promoter region through interaction with nuclear receptor corepressor 2/histone deacetylase 3 for its repression. In addition, activation of TLR9-mediated NF-kB and MAPK and nuclear translocation of IRF7 were greatly enhanced by MYC depletion. Pharmaceutical inhibition of MYC recovered IRF7 expression, further confirming the negative role of MYC in the antiviral response by pDC. Therefore, our results identify the novel immunomodulatory role of MYC in human pDC and may add to our understanding of aberrant pDC function in cancer and autoimmune disease.

Original languageEnglish (US)
Pages (from-to)3348-3359
Number of pages12
JournalJournal of Immunology
Volume197
Issue number8
DOIs
StatePublished - Oct 15 2016

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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