Mouse TIGIT inhibits NK-cell cytotoxicity upon interaction with PVR

Noa Stanietsky, Tihana Lenac Rovis, Ariella Glasner, Einat Seidel, Pinchas Tsukerman, Rachel Yamin, Jonatan Enk, Stipan Jonjic, Ofer Mandelboim*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

193 Scopus citations

Abstract

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.

Original languageAmerican English
Pages (from-to)2138-2150
Number of pages13
JournalEuropean Journal of Immunology
Volume43
Issue number8
DOIs
StatePublished - Aug 2013

Keywords

  • NK cells
  • PVR
  • TIGIT

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