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

EBI3 regulates the NK cell response to mouse cytomegalovirus infection.

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Department of Microbiology and Immunology, University of California, San Francisco, CA 94143.
Department of Microbiology and Immunology, Stanford University, Palo Alto, CA 94304.
Department of Systems Biology, Center for Biological Sequence Analysis, Technical University of Denmark, Lyngby DK-2800, Denmark.
Department of Microbiology and Immunology, University of California, San Francisco, CA 94143;
Parker Institute for Cancer Immunotherapy, San Francisco, CA 94143.


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.


EBI3; cytomegalovirus; natural killer cell

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