Inflammatory monocytes and NK cells play a crucial role in DNAM-1-dependent control of cytomegalovirus infection

J Exp Med. 2016 Aug 22;213(9):1835-50. doi: 10.1084/jem.20151899. Epub 2016 Aug 8.


The poliovirus receptor (PVR) is a ubiquitously expressed glycoprotein involved in cellular adhesion and immune response. It engages the activating receptor DNAX accessory molecule (DNAM)-1, the inhibitory receptor TIGIT, and the CD96 receptor with both activating and inhibitory functions. Human cytomegalovirus (HCMV) down-regulates PVR expression, but the significance of this viral function in vivo remains unknown. Here, we demonstrate that mouse CMV (MCMV) also down-regulates the surface PVR. The m20.1 protein of MCMV retains PVR in the endoplasmic reticulum and promotes its degradation. A MCMV mutant lacking the PVR inhibitor was attenuated in normal mice but not in mice lacking DNAM-1. This attenuation was partially reversed by NK cell depletion, whereas the simultaneous depletion of mononuclear phagocytes abolished the virus control. This effect was associated with the increased expression of DNAM-1, whereas TIGIT and CD96 were absent on these cells. An increased level of proinflammatory cytokines in sera of mice infected with the virus lacking the m20.1 and an increased production of iNOS by inflammatory monocytes was observed. Blocking of CCL2 or the inhibition of iNOS significantly increased titer of the virus lacking m20.1. In this study, we have demonstrated that inflammatory monocytes, together with NK cells, are essential in the early control of CMV through the DNAM-1-PVR pathway.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antigens, Differentiation, T-Lymphocyte / physiology*
  • Cytomegalovirus Infections / etiology*
  • Cytomegalovirus Infections / immunology
  • Interleukin-12 / biosynthesis
  • Killer Cells, Natural / physiology*
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Monocytes / physiology*
  • Nitric Oxide Synthase Type II / physiology
  • Receptors, Virus / antagonists & inhibitors
  • Receptors, Virus / physiology


  • Antigens, Differentiation, T-Lymphocyte
  • CD226 antigen
  • Receptors, Virus
  • poliovirus receptor
  • Interleukin-12
  • Nitric Oxide Synthase Type II
  • Nos2 protein, mouse