The Interaction of TIGIT with PVR and PVRL2 Inhibits Human NK Cell Cytotoxicity

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 106; no. 42; pp. 17858 - 17863
• Main Authors: Stanietsky, Noa, Simic, Hrvoje, Arapovic, Jurica, Toporik, Amir, Levy, Ofer, Novik, Amit, Levine, Zurit, Beiman, Meirav, Dassa, Liat, Achdout, Hagit, Stern-Ginossar, Noam, Tsukerman, Pinhas, Jonjic, Stipan, Mandelboim, Ofer
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 20.10.2009; National Acad Sciences
• Subjects: Animals; Antibodies; Binding sites; Biological Sciences; Cell Adhesion Molecules - chemistry; Cell Adhesion Molecules - metabolism; Cell Line; Cell lines; Cells; Cytotoxicity; Cytotoxicity, Immunologic; Fibroblasts; Histocompatibility Antigens Class I - metabolism; Histograms; 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; Natural killer cells; Nectins; Protein Binding; Protein Interaction Domains and Motifs; Proteins; Receptors; 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; T lymphocytes; Toxicity; Tumors
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.0903474106

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 cytoxicity thus providing an "alternative self" mechanism for MHC class I inhibition.