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

J Exp Med. 2016 Sep 19;213(10):2065-80. doi: 10.1084/jem.20160248. Epub 2016 Sep 12.


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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, N.I.H., Extramural

MeSH terms

  • Antigen Presentation
  • B-Lymphocytes / immunology
  • B-Lymphocytes / virology
  • CD4-Positive T-Lymphocytes / immunology*
  • Cell Death
  • Cell Differentiation
  • Cell Membrane / metabolism
  • Cytokines / metabolism
  • 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


  • Cytokines
  • Inflammation Mediators
  • MicroRNAs
  • Peptides
  • Receptors, Cell Surface
  • Interleukin-12

Associated data

  • GENBANK/AJ507799