title: Transcriptional Repression of IFN Regulatory Factor 7 by MYC Is Critical for Type I IFN Production in Human Plasmacytoid Dendritic Cells.
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-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.
authors.affiliation: Baylor Institute for Immunology Research, Dallas, TX 75204; and Yong-Jun.liu@sanofi.com TaeWhan.Kim@BSWHealth.org.
authors.forename: Tae Whan
authors.initials: TW
authors.lastname: Kim
authors.affiliation: Baylor Institute for Immunology Research, Dallas, TX 75204; and.
authors.forename: Seunghee
authors.initials: S
authors.lastname: Hong
authors.affiliation: Baylor Institute for Immunology Research, Dallas, TX 75204; and.
authors.forename: Yin
authors.initials: Y
authors.lastname: Lin
authors.affiliation: Baylor Institute for Immunology Research, Dallas, TX 75204; and.
authors.forename: Elise
authors.identifier: 0000-0003-2156-334X
authors.initials: E
authors.lastname: Murat
authors.affiliation: Baylor Institute for Immunology Research, Dallas, TX 75204; and.
authors.forename: HyeMee
authors.initials: H
authors.lastname: Joo
authors.affiliation: Sanofi, Cambridge, MA 02139.
authors.forename: Taeil
authors.initials: T
authors.lastname: Kim
authors.affiliation: Baylor Institute for Immunology Research, Dallas, TX 75204; and.
authors.forename: Virginia
authors.initials: V
authors.lastname: Pascual
authors.affiliation: Baylor Institute for Immunology Research, Dallas, TX 75204; and Yong-Jun.liu@sanofi.com TaeWhan.Kim@BSWHealth.org.|Sanofi, Cambridge, MA 02139.
authors.forename: Yong-Jun
authors.initials: YJ
authors.lastname: Liu
mesh_terms: D002478:Cells, Cultured; D003713:Dendritic Cells / Q000276:immunology / Q000378:metabolism*; D006801:Humans; D050839:Interferon Regulatory Factor-7 / Q000096:biosynthesis / Q000235:genetics*; D007370:Interferon Type I / Q000096:biosynthesis* / Q000276:immunology; D016271:Proto-Oncogene Proteins c-myc / Q000037:antagonists & inhibitors / Q000276:immunology / Q000378:metabolism*; D014158:Transcription, Genetic
chemical_list: D050839:Interferon Regulatory Factor-7; D007370:Interferon Type I; D016271:Proto-Oncogene Proteins c-myc