Transcriptional Repression of IFN Regulatory Factor 7 by MYC Is Critical for Type I IFN Production in Human Plasmacytoid Dendritic Cells.

TitleTranscriptional Repression of IFN Regulatory Factor 7 by MYC Is Critical for Type I IFN Production in Human Plasmacytoid Dendritic Cells.
Publication TypeJournal Article
Year of Publication2016
AuthorsKim TWhan, Hong S, Lin Y, Murat E, Joo HM, Kim T, Pascual V, Liu Y-J
JournalJ Immunol
Date Published2016 10 15
KeywordsCells, Cultured, Dendritic Cells, Humans, Interferon Regulatory Factor-7, Interferon Type I, Proto-Oncogene Proteins c-myc, Transcription, Genetic

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-κB 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.

Custom 1

Alternate JournalJ. Immunol.
PubMed ID27630164
PubMed Central IDPMC5101139
Grant ListR01 AI097348 / AI / NIAID NIH HHS / United States

Weill Cornell Medicine Gale and Ira Drukier Institute for Children's Health 413 E. 69th Street New York, NY 10021