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

• DOI: 10.1084/jem.20160248
• Publication Date: 2016-09-12T14:07:31Z
• Authors: Takanobu Tagawa; Manuel Albanese; Mickaël Bouvet; Andreas Moosmann; Josef Mautner; Vigo Heissmeyer; Christina Zielinski; Dominik Lutter; Jonathan Hoser; Maximilian Hastre...; Mitch Hayes; Bill Sugden; Wolfgang Hammersc...
• Keywords: CD4-Positive T-Lymphocytes; 0301 basic medicine; Antigen Presentation; B-Lymphocytes; Herpesvirus 4, Human; Cell Death; Cell Membrane; Immunity; Cell Differentiation; Receptors, Cell Surface; Th1 Cells; Interleukin-12; 3. Good health; MicroRNAs; 03 medical and health sciences; HEK293 Cells; Species Specificity; Cytokines; Humans; Inflammation Mediators; Lysosomes; Peptides; Research Articles

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.