title: Epigenetic reprogramming of the type III interferon response potentiates antiviral activity and suppresses tumor growth.
abstract: Type III interferon (IFN-λ) exhibits potent antiviral activity similar to IFN-α/β, but in contrast to the ubiquitous expression of the IFN-α/β receptor, the IFN-λ receptor is restricted to cells of epithelial origin. Despite the importance of IFN-λ in tissue-specific antiviral immunity, the molecular mechanisms responsible for this confined receptor expression remain elusive. Here, we demonstrate that the histone deacetylase (HDAC) repression machinery mediates transcriptional silencing of the unique IFN-λ receptor subunit (IFNLR1) in a cell-type-specific manner. Importantly, HDAC inhibitors elevate receptor expression and restore sensitivity to IFN-λ in previously nonresponsive cells, thereby enhancing protection against viral pathogens. In addition, blocking HDAC activity renders nonresponsive cell types susceptible to the pro-apoptotic activity of IFN-λ, revealing the combination of HDAC inhibitors and IFN-λ to be a potential antitumor strategy. These results demonstrate that the type III IFN response may be therapeutically harnessed by epigenetic rewiring of the IFN-λ receptor expression program.
authors.affiliation: Department of Pathology, Yale University School of Medicine, New Haven, Connecticut, United States of America ; Microbiology Graduate Program, Yale University School of Medicine, New Haven, Connecticut, United States of America.
authors.forename: Siyuan
authors.initials: S
authors.lastname: Ding
authors.affiliation: Department of Immunobiology, Yale University School of Medicine, New Haven, Connecticut, United States of America.
authors.forename: William
authors.initials: W
authors.lastname: Khoury-Hanold
authors.affiliation: Department of Immunobiology, Yale University School of Medicine, New Haven, Connecticut, United States of America ; Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, Connecticut, United States of America.
authors.forename: Akiko
authors.initials: A
authors.lastname: Iwasaki
authors.affiliation: Department of Pathology, Yale University School of Medicine, New Haven, Connecticut, United States of America.
authors.forename: Michael D
authors.initials: MD
authors.lastname: Robek
mesh_terms: D000818:Animals; D017209:Apoptosis; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D018899:CpG Islands; D006224:Cricetinae; D003587:Cytomegalovirus / Q000187:drug effects / Q000502:physiology; D019175:DNA Methylation / Q000187:drug effects; D044127:Epigenesis, Genetic; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology / Q000821:virology; D018259:Herpesvirus 1, Human / Q000187:drug effects / Q000502:physiology; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology; D006655:Histone Deacetylases / Q000235:genetics / Q000378:metabolism; D054884:Host-Pathogen Interactions; D006801:Humans; D007371:Interferon-gamma / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D041681:NIH 3T3 Cells; D009928:Organ Specificity; D011401:Promoter Regions, Genetic; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D018121:Receptors, Cytokine / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D017471:Receptors, Interferon; D015398:Signal Transduction; D018116:Vesiculovirus / Q000187:drug effects / Q000502:physiology
chemical_list: D056572:Histone Deacetylase Inhibitors; C579640:IFNLR1 protein, human; D034741:RNA, Small Interfering; D018121:Receptors, Cytokine; D017471:Receptors, Interferon; D007371:Interferon-gamma; D006655:Histone Deacetylases