title: Mouse TIGIT inhibits NK-cell cytotoxicity upon interaction with PVR.
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.
authors.affiliation: The Lautenberg Center for General and Tumor Immunology, Institute for Medical Research Israel Canada, Hebrew University-Hadassah Medical School, Jerusalem, Israel.
authors.forename: Noa
authors.initials: N
authors.lastname: Stanietsky
authors.forename: Tihana Lenac
authors.initials: TL
authors.lastname: Rovis
authors.forename: Ariella
authors.initials: A
authors.lastname: Glasner
authors.forename: Einat
authors.initials: E
authors.lastname: Seidel
authors.forename: Pinchas
authors.initials: P
authors.lastname: Tsukerman
authors.forename: Rachel
authors.initials: R
authors.lastname: Yamin
authors.forename: Jonatan
authors.initials: J
authors.lastname: Enk
authors.forename: Stipan
authors.initials: S
authors.lastname: Jonjic
authors.forename: Ofer
authors.initials: O
authors.lastname: Mandelboim
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D000945:Antigens, Differentiation, T-Lymphocyte / Q000378:metabolism; D015815:Cell Adhesion Molecules / Q000378:metabolism*; D003602:Cytotoxicity, Immunologic; D015395:Histocompatibility Antigens Class I / Q000276:immunology; D007371:Interferon-gamma / Q000096:biosynthesis; D007694:Killer Cells, Natural / Q000276:immunology* / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D000075983:Nectins; D011971:Receptors, Immunologic / Q000737:chemistry / Q000378:metabolism*; D011991:Receptors, Virus / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D016415:Sequence Alignment; D015398:Signal Transduction; D020349:Surface Plasmon Resonance; D000098862:T Lineage-Specific Activation Antigen 1
chemical_list: D015703:Antigens, CD; D000945:Antigens, Differentiation, T-Lymphocyte; D000098862:T Lineage-Specific Activation Antigen 1; C116131:CD96 antigen; D015815:Cell Adhesion Molecules; D015395:Histocompatibility Antigens Class I; C000619016:Nectin2 protein, mouse; D000075983:Nectins; D011971:Receptors, Immunologic; D011991:Receptors, Virus; D011993:Recombinant Fusion Proteins; C556305:T cell Ig and ITIM domain protein, mouse; C066100:poliovirus receptor; D007371:Interferon-gamma
keywords: NK cells; PVR; TIGIT