Enveloped viruses disable innate immune responses in dendritic cells by direct activation of TAM receptors

Cell Host Microbe. 2013 Aug 14;14(2):136-47. doi: 10.1016/j.chom.2013.07.005.

Abstract

Upon activation by the ligands Gas6 and Protein S, Tyro3/Axl/Mer (TAM) receptor tyrosine kinases promote phagocytic clearance of apoptotic cells and downregulate immune responses initiated by Toll-like receptors and type I interferons (IFNs). Many enveloped viruses display the phospholipid phosphatidylserine on their membranes, through which they bind Gas6 and Protein S and engage TAM receptors. We find that ligand-coated viruses activate TAM receptors on dendritic cells (DCs), dampen type I IFN signaling, and thereby evade host immunity and promote infection. Upon virus challenge, TAM-deficient DCs display type I IFN responses that are elevated in comparison to wild-type cells. As a consequence, TAM-deficient DCs are relatively resistant to infection by flaviviruses and pseudotyped retroviruses, but infection can be restored with neutralizing type I IFN antibodies. Correspondingly, a TAM kinase inhibitor antagonizes the infection of wild-type DCs. Thus, TAM receptors are engaged by viruses in order to attenuate type I IFN signaling and represent potential therapeutic targets.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Cell Line
  • Dendritic Cells / immunology*
  • Flavivirus / immunology*
  • Humans
  • Immune Tolerance*
  • Immunity, Innate*
  • Interferon Type I / biosynthesis
  • Mice
  • Proto-Oncogene Proteins / genetics
  • Proto-Oncogene Proteins / metabolism
  • Receptor Protein-Tyrosine Kinases / genetics
  • Receptor Protein-Tyrosine Kinases / metabolism
  • Retroviridae / immunology*
  • Signal Transduction
  • c-Mer Tyrosine Kinase

Substances

  • Interferon Type I
  • Proto-Oncogene Proteins
  • Mertk protein, mouse
  • Receptor Protein-Tyrosine Kinases
  • Tyro3 protein, mouse
  • axl receptor tyrosine kinase
  • c-Mer Tyrosine Kinase