title: Epigenetic control of Ccr7 expression in distinct lineages of lung dendritic cells.
abstract: Adaptive immune responses to inhaled allergens are induced following CCR7-dependent migration of precursor of dendritic cell (pre-DC)-derived conventional DCs (cDCs) from the lung to regional lymph nodes. However, monocyte-derived (moDCs) in the lung express very low levels of Ccr7 and consequently do not migrate efficiently to LN. To investigate the molecular mechanisms that underlie this dichotomy, we studied epigenetic modifications at the Ccr7 locus of murine cDCs and moDCs. When expanded from bone marrow precursors, moDCs were enriched at the Ccr7 locus for trimethylation of histone 3 lysine 27 (H3K27me3), a modification associated with transcriptional repression. Similarly, moDCs prepared from the lung also displayed increased levels of H3K27me3 at the Ccr7 promoter compared with migratory cDCs from that organ. Analysis of DC progenitors revealed that epigenetic modification of Ccr7 does not occur early during DC lineage commitment because monocytes and pre-DCs both had low levels of Ccr7-associated H3K27me3. Rather, Ccr7 is gradually silenced during the differentiation of monocytes to moDCs. Thus, epigenetic modifications of the Ccr7 locus control the migration and therefore the function of DCs in vivo. These findings suggest that manipulating epigenetic mechanisms might be a novel approach to control DC migration and thereby improve DC-based vaccines and treat inflammatory diseases of the lung.
authors.affiliation: Department of Pediatrics, Duke University Medical Center, Durham, NC 27710;
authors.forename: Timothy P
authors.initials: TP
authors.lastname: Moran
authors.affiliation: Laboratory of Respiratory Biology, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC 27709; and.
authors.forename: Hideki
authors.initials: H
authors.lastname: Nakano
authors.affiliation: Laboratory of Molecular Carcinogenesis, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC 27709.
authors.forename: Hrisavgi D
authors.initials: HD
authors.lastname: Kondilis-Mangum
authors.affiliation: Laboratory of Molecular Carcinogenesis, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC 27709.
authors.forename: Paul A
authors.initials: PA
authors.lastname: Wade
authors.affiliation: Laboratory of Respiratory Biology, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC 27709; and cookd@niehs.nih.gov.
authors.forename: Donald N
authors.initials: DN
authors.lastname: Cook
mesh_terms: D000818:Animals; D001854:Bone Marrow Cells / Q000166:cytology / Q000276:immunology; D002454:Cell Differentiation; D019070:Cell Lineage / Q000276:immunology; D002465:Cell Movement; D049109:Cell Proliferation; D003713:Dendritic Cells / Q000166:cytology / Q000276:immunology*; D044127:Epigenesis, Genetic; D006657:Histones / Q000235:genetics* / Q000276:immunology; D008168:Lung / Q000166:cytology / Q000276:immunology*; D008198:Lymph Nodes / Q000166:cytology / Q000276:immunology; D008745:Methylation; D051379:Mice; D008822:Mice, Transgenic; D009000:Monocytes / Q000166:cytology / Q000276:immunology*; D061251:Primary Cell Culture; D011401:Promoter Regions, Genetic; D054400:Receptors, CCR7 / Q000235:genetics* / Q000276:immunology; D015398:Signal Transduction; D014158:Transcription, Genetic
chemical_list: C515371:Ccr7 protein, mouse; D006657:Histones; D054400:Receptors, CCR7