Epstein-Barr viral miRNAs inhibit antiviral CD4+ T cell responses targeting IL-12 and peptide processing

• Published in: The Journal of experimental medicine Vol. 213; no. 10; pp. 2065 - 2080
• Main Authors: Tagawa, Takanobu, Albanese, Manuel, Bouvet, Mickaël, Moosmann, Andreas, Mautner, Josef, Heissmeyer, Vigo, Zielinski, Christina, Lutter, Dominik, Hoser, Jonathan, Hastreiter, Maximilian, Hayes, Mitch, Sugden, Bill, Hammerschmidt, Wolfgang
• Format: Journal Article
• Language: English
• Published: United States The Rockefeller University Press 19.09.2016
• Subjects: Antigen Presentation; B-Lymphocytes - immunology; B-Lymphocytes - virology; CD4-Positive T-Lymphocytes - immunology; Cell Death; Cell Differentiation; Cell Membrane - metabolism; Cytokines - metabolism; Epstein-Barr virus; HEK293 Cells; Herpesvirus 4, Human - genetics; Humans; Immunity; Inflammation Mediators - metabolism; Interleukin-12 - metabolism; Lysosomes - metabolism; MicroRNAs - genetics; MicroRNAs - metabolism; Peptides - metabolism; Receptors, Cell Surface - metabolism; Species Specificity; Th1 Cells - cytology; Th1 Cells - immunology
• ISSN: 0022-1007; 1540-9538
• DOI: 10.1084/jem.20160248

Epstein-Barr virus (EBV) is a tumor virus that establishes lifelong infection in most of humanity, despite eliciting strong and stable virus-specific immune responses. EBV encodes at least 44 miRNAs, most of them with unknown function. Here, we show that multiple EBV miRNAs modulate immune recognition of recently infected primary B cells, EBV's natural target cells. EBV miRNAs collectively and specifically suppress release of proinflammatory cytokines such as IL-12, repress differentiation of naive CD4(+) T cells to Th1 cells, interfere with peptide processing and presentation on HLA class II, and thus reduce activation of cytotoxic EBV-specific CD4(+) effector T cells and killing of infected B cells. Our findings identify a previously unknown viral strategy of immune evasion. By rapidly expressing multiple miRNAs, which are themselves nonimmunogenic, EBV counteracts recognition by CD4(+) T cells and establishes a program of reduced immunogenicity in recently infected B cells, allowing the virus to express viral proteins required for establishment of life-long infection.