EBI3 regulates the NK cell response to mouse cytomegalovirus infection.

Abstract

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 (<i>Ebi3</i>^<i>-/-</i> ) C57BL/6 (B6) mice during MCMV infection. Furthermore, comparable levels of early viral replication in spleen and liver were observed in MCMV-infected <i>Ebi3</i>^<i>-/-</i> and wild-type (WT) B6 mice. Interestingly, the viral load in salivary glands and oral lavage was strongly decreased in the MCMV-infected <i>Ebi3</i>^<i>-/-</i> 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 <i>Ebi3</i>^-/- 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.