EBI3 regulates the NK cell response to mouse cytomegalovirus infection

Proc Natl Acad Sci U S A. 2017 Feb 14;114(7):1625-1630. doi: 10.1073/pnas.1700231114. Epub 2017 Jan 31.


Natural killer (NK) cells are key mediators in the control of cytomegalovirus infection. Here, we show that Epstein-Barr virus-induced 3 (EBI3) is expressed by human NK cells after NKG2D or IL-12 plus IL-18 stimulation and by mouse NK cells during mouse cytomegalovirus (MCMV) infection. The induction of EBI3 protein expression in mouse NK cells is a late activation event. Thus, early activation events of NK cells, such as IFNγ production and CD69 expression, were not affected in EBI3-deficient (Ebi3-/- ) C57BL/6 (B6) mice during MCMV infection. Furthermore, comparable levels of early viral replication in spleen and liver were observed in MCMV-infected Ebi3-/- and wild-type (WT) B6 mice. Interestingly, the viral load in salivary glands and oral lavage was strongly decreased in the MCMV-infected Ebi3-/- B6 mice, suggesting that EBI3 plays a role in the establishment of MCMV latency. We detected a decrease in the sustained IL-10 production by NK cells and lower serum levels of IL-10 in the MCMV-infected Ebi3-/- B6 mice. Furthermore, we observed an increase in dendritic cell maturation markers and an increase in activated CD8+ T cells. Thus, EBI3 dampens the immune response against MCMV infection, resulting in prolonged viral persistence.

Keywords: EBI3; cytomegalovirus; natural killer cell.

Publication types

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

MeSH terms

  • Animals
  • Cell Line
  • Cells, Cultured
  • Cytomegalovirus Infections / immunology*
  • Cytomegalovirus Infections / metabolism
  • Cytomegalovirus Infections / virology
  • Gene Expression / immunology
  • Host-Pathogen Interactions / immunology
  • Humans
  • Interleukin-12 / immunology
  • Interleukin-12 / metabolism
  • Interleukin-18 / immunology
  • Interleukin-18 / metabolism
  • Killer Cells, Natural / immunology*
  • Killer Cells, Natural / metabolism
  • Killer Cells, Natural / virology
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Minor Histocompatibility Antigens / genetics
  • Minor Histocompatibility Antigens / immunology*
  • Minor Histocompatibility Antigens / metabolism
  • Muromegalovirus / immunology*
  • Muromegalovirus / physiology
  • Receptors, Cytokine / genetics
  • Receptors, Cytokine / immunology*
  • Receptors, Cytokine / metabolism


  • Ebi3 protein, mouse
  • Interleukin-18
  • Minor Histocompatibility Antigens
  • Receptors, Cytokine
  • Interleukin-12