title: Repression of arginase-2 expression in dendritic cells by microRNA-155 is critical for promoting T cell proliferation.
abstract: Arginine, a semiessential amino acid implicated in diverse cellular processes, is a substrate for two arginases-Arg1 and Arg2-having different expression patterns and functions. Although appropriately regulated Arg1 expression is critical for immune responses, this has not been documented for Arg2. We show that Arg2 is the dominant enzyme in dendritic cells (DCs) and is repressed by microRNA-155 (miR155) during their maturation. miR155 is known to be strongly induced in various mouse and human DC subsets in response to diverse maturation signals, and miR155-deficient DCs exhibit an impaired ability to induce Ag-specific T cell responses. By means of expression profiling studies, we identified Arg2 mRNA as a novel miR155 target in mouse DCs. Abnormally elevated levels of Arg2 expression and activity were observed in activated miR155-deficient DCs. Conversely, overexpression of miR155 inhibited Arg2 expression. Bioinformatic and functional analyses confirmed that Arg2 mRNA is a direct target of miR155. Finally, in vitro and in vivo functional assays using DCs exhibiting deregulated Arg2 expression indicated that Arg2-mediated arginine depletion in the extracellular milieu impairs T cell proliferation. These results indicate that miR155-induced repression of Arg2 expression is critical for the ability of DCs to drive T cell activation by controlling arginine availability in the extracellular environment.
authors.affiliation: Department of Pathology and Immunology, Faculty of Medicine, University of Geneva, CH-1211 Geneva, Switzerland; and.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Dunand-Sauthier
authors.affiliation: Department of Pathology and Immunology, Faculty of Medicine, University of Geneva, CH-1211 Geneva, Switzerland; and.
authors.forename: Magali
authors.initials: M
authors.lastname: Irla
authors.affiliation: Department of Pathology and Immunology, Faculty of Medicine, University of Geneva, CH-1211 Geneva, Switzerland; and.
authors.forename: Stéphanie
authors.initials: S
authors.lastname: Carnesecchi
authors.affiliation: Department of Pathology and Immunology, Faculty of Medicine, University of Geneva, CH-1211 Geneva, Switzerland; and.
authors.forename: Queralt
authors.initials: Q
authors.lastname: Seguín-Estévez
authors.affiliation: Swiss Institute of Bioinformatics and Department of Medical Genetics and Development, Faculty of Medicine, University of Geneva, CH-1211 Geneva, Switzerland.
authors.forename: Charles E
authors.initials: CE
authors.lastname: Vejnar
authors.affiliation: Swiss Institute of Bioinformatics and Department of Medical Genetics and Development, Faculty of Medicine, University of Geneva, CH-1211 Geneva, Switzerland.
authors.forename: Evgeny M
authors.initials: EM
authors.lastname: Zdobnov
authors.affiliation: Department of Pathology and Immunology, Faculty of Medicine, University of Geneva, CH-1211 Geneva, Switzerland; and.
authors.forename: Marie-Laure
authors.initials: ML
authors.lastname: Santiago-Raber
authors.affiliation: Department of Pathology and Immunology, Faculty of Medicine, University of Geneva, CH-1211 Geneva, Switzerland; and walter.reith@unige.ch.
authors.forename: Walter
authors.initials: W
authors.lastname: Reith
mesh_terms: D000818:Animals; D001119:Arginase / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000235:genetics; D001120:Arginine / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D049109:Cell Proliferation; D003713:Dendritic Cells / Q000201:enzymology* / Q000276:immunology; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000276:immunology; D057809:HEK293 Cells; D006801:Humans; D008213:Lymphocyte Activation / Q000235:genetics / Q000276:immunology*; D051379:Mice; D018345:Mice, Knockout; D035683:MicroRNAs / Q000235:genetics*; D012323:RNA Processing, Post-Transcriptional; D012333:RNA, Messenger / Q000235:genetics
chemical_list: D035683:MicroRNAs; C532623:Mirn155 microRNA, mouse; D012333:RNA, Messenger; D001120:Arginine; C481673:Arg2 protein, mouse; D001119:Arginase