The study investigates the interaction between TIGIT, a protein expressed on natural killer (NK) cells, and PVR and PVRL2, which are ligands for TIGIT. The authors found that TIGIT directly inhibits NK cell cytotoxicity through its ITIM motif, and that this inhibition is dependent on the ITIM. They also showed that TIGIT counteracts the killing of tumor cells by NK cells and protects normal cells from NK-mediated cytotoxicity, providing an "alternative self" mechanism for MHC class I inhibition. Additionally, they demonstrated that PVR and PVRL2 are ligands for TIGIT, with PVR being the strongest binder, followed by PVRL2, but not PVRL3. The study highlights the role of TIGIT in regulating NK cell activity and its potential implications in immune evasion and self-tolerance.The study investigates the interaction between TIGIT, a protein expressed on natural killer (NK) cells, and PVR and PVRL2, which are ligands for TIGIT. The authors found that TIGIT directly inhibits NK cell cytotoxicity through its ITIM motif, and that this inhibition is dependent on the ITIM. They also showed that TIGIT counteracts the killing of tumor cells by NK cells and protects normal cells from NK-mediated cytotoxicity, providing an "alternative self" mechanism for MHC class I inhibition. Additionally, they demonstrated that PVR and PVRL2 are ligands for TIGIT, with PVR being the strongest binder, followed by PVRL2, but not PVRL3. The study highlights the role of TIGIT in regulating NK cell activity and its potential implications in immune evasion and self-tolerance.