title: A novel Cd8-cis-regulatory element preferentially directs expression in CD44hiCD62L+ CD8+ T cells and in CD8αα+ dendritic cells.
abstract: CD8 coreceptor expression is dynamically regulated during thymocyte development and is tightly controlled by the activity of at least 5 different cis-regulatory elements. Despite the detailed characterization of the Cd8 loci, the regulation of the complex expression pattern of CD8 cannot be fully explained by the activity of the known Cd8 enhancers. In this study, we revisited the Cd8ab gene complex with bioinformatics and transgenic reporter gene expression approaches to search for additional Cd8 cis-regulatory elements. This led to the identification of an ECR (ECR-4), which in transgenic reporter gene expression assays, directed expression preferentially in CD44(hi)CD62L(+) CD8(+) T cells, including innate-like CD8(+) T cells. ECR-4, designated as Cd8 enhancer E8VI, was bound by Runx/CBFβ complexes and Bcl11b, indicating that E8VI is part of the cis-regulatory network that recruits transcription factors to the Cd8ab gene complex in CD8(+) T cells. Transgenic reporter expression was maintained in LCMV-specific CD8(+) T cells upon infection, although short-term, in vitro activation led to a down-regulation of E8VI activity. Finally, E8VI directed transgene expression also in CD8αα(+) DCs but not in CD8αα-expressing IELs. Taken together, we have identified a novel Cd8 enhancer that directs expression in CD44(hi)CD62L(+) CD8(+) T cells, including innate-like and antigen-specific effector/memory CD8(+) T cells and in CD8αα(+) DCs, and thus, our data provide further insight into the cis-regulatory networks that control CD8 expression.
authors.affiliation: *Division of Immunobiology, Institute of Immunology, Center for Pathophysiology, Infectiology and Immunology, Department of Medical Biochemistry, Max F. Perutz Laboratories, Vienna Biocenter, and Institute of Vascular Biology, Medical University of Vienna, Austria; Laboratory for Transcriptional Regulation, RIKEN Center for Integrative Medical Sciences, Yokohama, Kanagawa, Japan; and CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria.
authors.forename: Shinya
authors.initials: S
authors.lastname: Sakaguchi
authors.affiliation: *Division of Immunobiology, Institute of Immunology, Center for Pathophysiology, Infectiology and Immunology, Department of Medical Biochemistry, Max F. Perutz Laboratories, Vienna Biocenter, and Institute of Vascular Biology, Medical University of Vienna, Austria; Laboratory for Transcriptional Regulation, RIKEN Center for Integrative Medical Sciences, Yokohama, Kanagawa, Japan; and CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria.
authors.forename: Matthias
authors.initials: M
authors.lastname: Hombauer
authors.affiliation: *Division of Immunobiology, Institute of Immunology, Center for Pathophysiology, Infectiology and Immunology, Department of Medical Biochemistry, Max F. Perutz Laboratories, Vienna Biocenter, and Institute of Vascular Biology, Medical University of Vienna, Austria; Laboratory for Transcriptional Regulation, RIKEN Center for Integrative Medical Sciences, Yokohama, Kanagawa, Japan; and CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria.
authors.forename: Hammad
authors.initials: H
authors.lastname: Hassan
authors.affiliation: *Division of Immunobiology, Institute of Immunology, Center for Pathophysiology, Infectiology and Immunology, Department of Medical Biochemistry, Max F. Perutz Laboratories, Vienna Biocenter, and Institute of Vascular Biology, Medical University of Vienna, Austria; Laboratory for Transcriptional Regulation, RIKEN Center for Integrative Medical Sciences, Yokohama, Kanagawa, Japan; and CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria.
authors.forename: Hirokazu
authors.initials: H
authors.lastname: Tanaka
authors.affiliation: *Division of Immunobiology, Institute of Immunology, Center for Pathophysiology, Infectiology and Immunology, Department of Medical Biochemistry, Max F. Perutz Laboratories, Vienna Biocenter, and Institute of Vascular Biology, Medical University of Vienna, Austria; Laboratory for Transcriptional Regulation, RIKEN Center for Integrative Medical Sciences, Yokohama, Kanagawa, Japan; and CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria.
authors.forename: Nighat
authors.initials: N
authors.lastname: Yasmin
authors.affiliation: *Division of Immunobiology, Institute of Immunology, Center for Pathophysiology, Infectiology and Immunology, Department of Medical Biochemistry, Max F. Perutz Laboratories, Vienna Biocenter, and Institute of Vascular Biology, Medical University of Vienna, Austria; Laboratory for Transcriptional Regulation, RIKEN Center for Integrative Medical Sciences, Yokohama, Kanagawa, Japan; and CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria.
authors.forename: Yoshinori
authors.initials: Y
authors.lastname: Naoe
authors.affiliation: *Division of Immunobiology, Institute of Immunology, Center for Pathophysiology, Infectiology and Immunology, Department of Medical Biochemistry, Max F. Perutz Laboratories, Vienna Biocenter, and Institute of Vascular Biology, Medical University of Vienna, Austria; Laboratory for Transcriptional Regulation, RIKEN Center for Integrative Medical Sciences, Yokohama, Kanagawa, Japan; and CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria.
authors.forename: Ivan
authors.initials: I
authors.lastname: Bilic
authors.affiliation: *Division of Immunobiology, Institute of Immunology, Center for Pathophysiology, Infectiology and Immunology, Department of Medical Biochemistry, Max F. Perutz Laboratories, Vienna Biocenter, and Institute of Vascular Biology, Medical University of Vienna, Austria; Laboratory for Transcriptional Regulation, RIKEN Center for Integrative Medical Sciences, Yokohama, Kanagawa, Japan; and CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria.
authors.forename: Mirjam A
authors.initials: MA
authors.lastname: Moser
authors.affiliation: *Division of Immunobiology, Institute of Immunology, Center for Pathophysiology, Infectiology and Immunology, Department of Medical Biochemistry, Max F. Perutz Laboratories, Vienna Biocenter, and Institute of Vascular Biology, Medical University of Vienna, Austria; Laboratory for Transcriptional Regulation, RIKEN Center for Integrative Medical Sciences, Yokohama, Kanagawa, Japan; and CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria.
authors.forename: Daniela
authors.initials: D
authors.lastname: Hainberger
authors.affiliation: *Division of Immunobiology, Institute of Immunology, Center for Pathophysiology, Infectiology and Immunology, Department of Medical Biochemistry, Max F. Perutz Laboratories, Vienna Biocenter, and Institute of Vascular Biology, Medical University of Vienna, Austria; Laboratory for Transcriptional Regulation, RIKEN Center for Integrative Medical Sciences, Yokohama, Kanagawa, Japan; and CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria.
authors.forename: Herbert
authors.initials: H
authors.lastname: Mayer
authors.affiliation: *Division of Immunobiology, Institute of Immunology, Center for Pathophysiology, Infectiology and Immunology, Department of Medical Biochemistry, Max F. Perutz Laboratories, Vienna Biocenter, and Institute of Vascular Biology, Medical University of Vienna, Austria; Laboratory for Transcriptional Regulation, RIKEN Center for Integrative Medical Sciences, Yokohama, Kanagawa, Japan; and CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria.
authors.forename: Christian
authors.initials: C
authors.lastname: Seiser
authors.affiliation: *Division of Immunobiology, Institute of Immunology, Center for Pathophysiology, Infectiology and Immunology, Department of Medical Biochemistry, Max F. Perutz Laboratories, Vienna Biocenter, and Institute of Vascular Biology, Medical University of Vienna, Austria; Laboratory for Transcriptional Regulation, RIKEN Center for Integrative Medical Sciences, Yokohama, Kanagawa, Japan; and CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria.
authors.forename: Andreas
authors.initials: A
authors.lastname: Bergthaler
authors.affiliation: *Division of Immunobiology, Institute of Immunology, Center for Pathophysiology, Infectiology and Immunology, Department of Medical Biochemistry, Max F. Perutz Laboratories, Vienna Biocenter, and Institute of Vascular Biology, Medical University of Vienna, Austria; Laboratory for Transcriptional Regulation, RIKEN Center for Integrative Medical Sciences, Yokohama, Kanagawa, Japan; and CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria.
authors.forename: Ichiro
authors.initials: I
authors.lastname: Taniuchi
authors.affiliation: *Division of Immunobiology, Institute of Immunology, Center for Pathophysiology, Infectiology and Immunology, Department of Medical Biochemistry, Max F. Perutz Laboratories, Vienna Biocenter, and Institute of Vascular Biology, Medical University of Vienna, Austria; Laboratory for Transcriptional Regulation, RIKEN Center for Integrative Medical Sciences, Yokohama, Kanagawa, Japan; and CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria wilfried.ellmeier@meduniwien.ac.at.
authors.forename: Wilfried
authors.initials: W
authors.lastname: Ellmeier
mesh_terms: D000818:Animals; D001483:Base Sequence; D016827:CD8 Antigens / Q000096:biosynthesis / Q000235:genetics*; D018414:CD8-Positive T-Lymphocytes / Q000378:metabolism*; D002874:Chromosome Mapping; D017124:Conserved Sequence; D050677:Core Binding Factor Alpha 3 Subunit / Q000378:metabolism; D003713:Dendritic Cells / Q000378:metabolism*; D004285:Dogs; D004742:Enhancer Elements, Genetic; D005786:Gene Expression Regulation; D017930:Genes, Reporter; D006801:Humans; D018960:Hyaluronan Receptors / Q000032:analysis; D007156:Immunologic Memory; D019041:L-Selectin / Q000032:analysis; D051379:Mice; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D025941:Protein Interaction Mapping; D051381:Rats; D012045:Regulatory Sequences, Nucleic Acid / Q000235:genetics*; D012097:Repressor Proteins / Q000378:metabolism; D016415:Sequence Alignment; D012689:Sequence Homology, Nucleic Acid; D013045:Species Specificity; D016176:T-Lymphocyte Subsets / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000378:metabolism
chemical_list: C511143:Bcl11b protein, mouse; D016827:CD8 Antigens; C409469:CD8 antigen, alpha chain; C476399:Cd44 protein, mouse; C526846:Cd8b1 protein, mouse; D050677:Core Binding Factor Alpha 3 Subunit; D018960:Hyaluronan Receptors; D012097:Repressor Proteins; C493730:Runx3 protein, mouse; D025521:Tumor Suppressor Proteins; D019041:L-Selectin
keywords: CD8 coreceptor; enhancer; gene expression; transgenics