The interaction of TIGIT with PVR and PVRL2 inhibits human NK cell cytotoxicity

Proc Natl Acad Sci U S A. 2009 Oct 20;106(42):17858-63. doi: 10.1073/pnas.0903474106. Epub 2009 Oct 7.


NK cell cytotoxicity is controlled by numerous NK inhibitory and activating receptors. Most of the inhibitory receptors bind MHC class I proteins and are expressed in a variegated fashion. It was recently shown that TIGIT, a new protein expressed by T and NK cells binds to PVR and PVR-like receptors and inhibits T cell activity indirectly through the manipulation of DC activity. Here, we show that TIGIT is expressed by all human NK cells, that it binds PVR and PVRL2 but not PVRL3 and that it inhibits NK cytotoxicity directly through its ITIM. Finally, we show that TIGIT counter inhibits the NK-mediated killing of tumor cells and protects normal cells from NK-mediated cytotoxicity thus providing an "alternative self" mechanism for MHC class I inhibition.

Publication types

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

MeSH terms

  • Animals
  • Cell Adhesion Molecules / chemistry
  • Cell Adhesion Molecules / metabolism*
  • Cell Line
  • Cytotoxicity, Immunologic*
  • Histocompatibility Antigens Class I / metabolism
  • Humans
  • In Vitro Techniques
  • Interleukin-2 Receptor beta Subunit / metabolism
  • Killer Cells, Natural / immunology*
  • Killer Cells, Natural / metabolism*
  • Ligands
  • Lymphocyte Subsets / immunology
  • Lymphocyte Subsets / metabolism
  • Mice
  • Nectins
  • Protein Binding
  • Protein Interaction Domains and Motifs
  • Receptors, Immunologic / chemistry
  • Receptors, Immunologic / genetics
  • Receptors, Immunologic / metabolism*
  • Receptors, Virus / chemistry
  • Receptors, Virus / genetics
  • Receptors, Virus / metabolism*
  • Recombinant Proteins / chemistry
  • Recombinant Proteins / genetics
  • Recombinant Proteins / metabolism


  • Cell Adhesion Molecules
  • Histocompatibility Antigens Class I
  • IL2RB protein, human
  • Interleukin-2 Receptor beta Subunit
  • Ligands
  • NECTIN3 protein, human
  • Nectin2 protein, mouse
  • Nectin3 protein, mouse
  • Nectins
  • Receptors, Immunologic
  • Receptors, Virus
  • Recombinant Proteins
  • TIGIT protein, human
  • poliovirus receptor