title: Transcriptional determinants of tolerogenic and immunogenic states during dendritic cell maturation.
abstract: Dendritic cells (DCs) promote either tolerogenic or immunogenic T cell responses, the latter upon sensing microbes. Using an in vitro system, we analyzed transcriptional determinants that enable mature DCs to direct these opposing T cell outcomes. In the absence of microbial products, the transcription factor interferon regulatory factor 4 (IRF4) promotes regulatory T cell (Treg) generation by enhancing expression of genes required for antigen presentation along with those for T cell tolerance. IRF4-deficient DCs were impaired for Treggeneration in vivo. When exposed to microbial stimuli, DCs activated nuclear factor (NF)-κB, which induced expression of a proinflammatory cytokine module that, along with the antigen presentation module, promoted the generation of effector T cells. NF-κB was, however, dispensable for Tregdevelopment. Chromatin profiling revealed transcriptional motifs associated with the divergent DC programs. Thus, DCs modulate their ability to prime tolerogenic or immunogenic T cells by expressing a core antigen presentation module that is overlaid by distinctive regulatory modules to promote either tolerance or immunity.
authors.affiliation: Department of Cancer Immunology, Genentech, South San Francisco, CA 94080.
authors.forename: Bryan
authors.initials: B
authors.lastname: Vander Lugt
authors.affiliation: Center for Autoimmune Genomics and Etiology, Divisions of Biomedical Informatics and Developmental Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229.
authors.forename: Jeremy
authors.initials: J
authors.lastname: Riddell
authors.affiliation: Institute for Systems and Genomics Biology, The University of Chicago, Chicago, IL 60637.|Department of Human Genetics, The University of Chicago, Chicago, IL 60637.
authors.forename: Aly A
authors.initials: AA
authors.lastname: Khan
authors.affiliation: Department of Bioinformatics and Computational Biology, Genentech, South San Francisco, CA 94080.
authors.forename: Jason A
authors.identifier: 0000-0002-5922-563X
authors.initials: JA
authors.lastname: Hackney
authors.affiliation: Department Translational Immunology, Genentech, South San Francisco, CA 94080.
authors.forename: Justin
authors.initials: J
authors.lastname: Lesch
authors.affiliation: Department Translational Immunology, Genentech, South San Francisco, CA 94080.
authors.forename: Jason
authors.initials: J
authors.lastname: DeVoss
authors.affiliation: Center for Autoimmune Genomics and Etiology, Divisions of Biomedical Informatics and Developmental Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229.
authors.forename: Matthew T
authors.initials: MT
authors.lastname: Weirauch
authors.affiliation: Center for Systems Immunology, Division of Immunobiology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229 harinder.singh@cchmc.org mellman.ira@gene.com.
authors.forename: Harinder
authors.initials: H
authors.lastname: Singh
authors.affiliation: Department of Cancer Immunology, Genentech, South San Francisco, CA 94080 harinder.singh@cchmc.org mellman.ira@gene.com.
authors.forename: Ira
authors.initials: I
authors.lastname: Mellman
mesh_terms: D000818:Animals; D017951:Antigen Presentation / Q000235:genetics / Q000276:immunology; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology; D016207:Cytokines / Q000378:metabolism; D003713:Dendritic Cells / Q000276:immunology* / Q000378:metabolism / Q000502:physiology*; D007108:Immune Tolerance / Q000235:genetics* / Q000276:immunology* / Q000502:physiology; D050835:Interferon Regulatory Factors / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000276:immunology / Q000378:metabolism / Q000502:physiology; D014158:Transcription, Genetic / Q000235:genetics* / Q000276:immunology; D000099218:Interferon Regulatory Factor-4
chemical_list: D016207:Cytokines; D050835:Interferon Regulatory Factors; D016328:NF-kappa B; D000099218:Interferon Regulatory Factor-4