title: Epstein-Barr virus microRNAs reduce immune surveillance by virus-specific CD8+ T cells.
abstract: Infection with Epstein-Barr virus (EBV) affects most humans worldwide and persists life-long in the presence of robust virus-specific T-cell responses. In both immunocompromised and some immunocompetent people, EBV causes several cancers and lymphoproliferative diseases. EBV transforms B cells in vitro and encodes at least 44 microRNAs (miRNAs), most of which are expressed in EBV-transformed B cells, but their functions are largely unknown. Recently, we showed that EBV miRNAs inhibit CD4+T-cell responses to infected B cells by targeting IL-12, MHC class II, and lysosomal proteases. Here we investigated whether EBV miRNAs also counteract surveillance by CD8+T cells. We have found that EBV miRNAs strongly inhibit recognition and killing of infected B cells by EBV-specific CD8+T cells through multiple mechanisms. EBV miRNAs directly target the peptide transporter subunit TAP2 and reduce levels of the TAP1 subunit, MHC class I molecules, and EBNA1, a protein expressed in most forms of EBV latency and a target of EBV-specific CD8+T cells. Moreover, miRNA-mediated down-regulation of the cytokine IL-12 decreases the recognition of infected cells by EBV-specific CD8+T cells. Thus, EBV miRNAs use multiple, distinct pathways, allowing the virus to evade surveillance not only by CD4+but also by antiviral CD8+T cells.
authors.affiliation: Research Unit Gene Vectors, German Research Center for Environmental Health, Helmholtz Zentrum München, D-81377 Munich, Germany; German Centre for Infection Research (DZIF), D-81377 Munich, Germany.
authors.forename: Manuel
authors.identifier: 0000-0002-4614-7599
authors.initials: M
authors.lastname: Albanese
authors.affiliation: Research Unit Gene Vectors, German Research Center for Environmental Health, Helmholtz Zentrum München, D-81377 Munich, Germany; German Centre for Infection Research (DZIF), D-81377 Munich, Germany.
authors.forename: Takanobu
authors.initials: T
authors.lastname: Tagawa
authors.affiliation: Research Unit Gene Vectors, German Research Center for Environmental Health, Helmholtz Zentrum München, D-81377 Munich, Germany; German Centre for Infection Research (DZIF), D-81377 Munich, Germany.
authors.forename: Mickaël
authors.initials: M
authors.lastname: Bouvet
authors.affiliation: Research Unit Gene Vectors, German Research Center for Environmental Health, Helmholtz Zentrum München, D-81377 Munich, Germany; German Centre for Infection Research (DZIF), D-81377 Munich, Germany.
authors.forename: Liridona
authors.initials: L
authors.lastname: Maliqi
authors.affiliation: Institute for Diabetes and Obesity, German Research Center for Environmental Health, Helmholtz Zentrum München, D-85748 Garching, Germany.
authors.forename: Dominik
authors.initials: D
authors.lastname: Lutter
authors.affiliation: Institute of Bioinformatics and System Biology, German Research Center for Environmental Health, Helmholtz Zentrum München, D-85764 Neuherberg, Germany.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Hoser
authors.affiliation: Institute of Bioinformatics and System Biology, German Research Center for Environmental Health, Helmholtz Zentrum München, D-85764 Neuherberg, Germany.
authors.forename: Maximilian
authors.initials: M
authors.lastname: Hastreiter
authors.affiliation: McArdle Laboratory for Cancer Research, University of Wisconsin-Madison, Madison, WI 53705.
authors.forename: Mitch
authors.initials: M
authors.lastname: Hayes
authors.affiliation: McArdle Laboratory for Cancer Research, University of Wisconsin-Madison, Madison, WI 53705.
authors.forename: Bill
authors.initials: B
authors.lastname: Sugden
authors.affiliation: Research Unit Gene Vectors, German Research Center for Environmental Health, Helmholtz Zentrum München, D-81377 Munich, Germany; German Centre for Infection Research (DZIF), D-81377 Munich, Germany.
authors.forename: Larissa
authors.initials: L
authors.lastname: Martin
authors.affiliation: Research Unit Gene Vectors, German Research Center for Environmental Health, Helmholtz Zentrum München, D-81377 Munich, Germany; German Centre for Infection Research (DZIF), D-81377 Munich, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Moosmann
authors.affiliation: Research Unit Gene Vectors, German Research Center for Environmental Health, Helmholtz Zentrum München, D-81377 Munich, Germany; German Centre for Infection Research (DZIF), D-81377 Munich, Germany; hammerschmidt@helmholtz-muenchen.de.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Hammerschmidt
mesh_terms: D017951:Antigen Presentation; D001402:B-Lymphocytes / Q000276:immunology / Q000378:metabolism / Q000821:virology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D002460:Cell Line; D002470:Cell Survival / Q000276:immunology; D016207:Cytokines / Q000378:metabolism; D003602:Cytotoxicity, Immunologic; D018984:Epitopes, T-Lymphocyte / Q000378:metabolism; D020031:Epstein-Barr Virus Infections / Q000276:immunology* / Q000378:metabolism / Q000821:virology*; D015967:Gene Expression Regulation, Viral; D004854:Herpesvirus 4, Human / Q000235:genetics* / Q000276:immunology*; D015395:Histocompatibility Antigens Class I / Q000276:immunology / Q000378:metabolism; D006801:Humans; D057131:Immune Evasion; D007157:Immunologic Surveillance / Q000235:genetics*; D035683:MicroRNAs / Q000235:genetics*; D012367:RNA, Viral / Q000235:genetics*; D018121:Receptors, Cytokine / Q000378:metabolism
chemical_list: D016207:Cytokines; D018984:Epitopes, T-Lymphocyte; D015395:Histocompatibility Antigens Class I; D035683:MicroRNAs; D012367:RNA, Viral; D018121:Receptors, Cytokine
keywords: CD8 T cells; adaptive immunity; herpesvirus; immune evasion; microRNA