Mouse TIGIT inhibits NK-cell cytotoxicity upon interaction with PVR

Eur J Immunol. 2013 Aug;43(8):2138-50. doi: 10.1002/eji.201243072. Epub 2013 Jul 4.


The activity of natural killer (NK) cells is controlled by a balance of signals derived from inhibitory and activating receptors. TIGIT is a novel inhibitory receptor, recently shown in humans to interact with two ligands: PVR and Nectin2 and to inhibit human NK-cell cytotoxicity. Whether mouse TIGIT (mTIGIT) inhibits mouse NK-cell cytotoxicity is unknown. Here we show that mTIGIT is expressed by mouse NK cells and interacts with mouse PVR. Using mouse and human Ig fusion proteins we show that while the human TIGIT (hTIGIT) cross-reacts with mouse PVR (mPVR), the binding of mTIGIT is restricted to mPVR. We further demonstrate using surface plasmon resonance (SPR) and staining with Ig fusion proteins that mTIGIT binds to mPVR with higher affinity than the co-stimulatory PVR-binding receptor mouse DNAM1 (mDNAM1). Functionally, we show that triggering of mTIGIT leads to the inhibition of NK-cell cytotoxicity, that IFN-γ secretion is enhanced when mTIGIT is blocked and that the TIGIT-mediated inhibition is dominant over the signals delivered by the PVR-binding co-stimulatory receptors. Additionally, we identify the inhibitory motif responsible for mTIGIT inhibition. In conclusion, we show that TIGIT is a powerful inhibitory receptor for mouse NK cells.

Keywords: NK cells; PVR; TIGIT.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Antigens, CD / metabolism
  • Antigens, Differentiation, T-Lymphocyte / metabolism
  • Cell Adhesion Molecules / metabolism*
  • Cytotoxicity, Immunologic*
  • Histocompatibility Antigens Class I / immunology
  • Interferon-gamma / biosynthesis
  • Killer Cells, Natural / immunology*
  • Killer Cells, Natural / metabolism*
  • Mice
  • Mice, Inbred C57BL
  • Nectins
  • Receptors, Immunologic / chemistry
  • Receptors, Immunologic / metabolism*
  • Receptors, Virus / metabolism*
  • Recombinant Fusion Proteins / metabolism
  • Sequence Alignment
  • Signal Transduction
  • Surface Plasmon Resonance


  • Antigens, CD
  • Antigens, Differentiation, T-Lymphocyte
  • CD226 antigen
  • CD96 antigen
  • Cell Adhesion Molecules
  • Histocompatibility Antigens Class I
  • Nectin2 protein, mouse
  • Nectins
  • Receptors, Immunologic
  • Receptors, Virus
  • Recombinant Fusion Proteins
  • T cell Ig and ITIM domain protein, mouse
  • poliovirus receptor
  • Interferon-gamma