Recognition of nectin-2 by the natural killer cell receptor T cell immunoglobulin and ITIM domain (TIGIT)

摘要

T cell immunoglobulin and ITIM domain (TIGIT) is an inhibitory receptor expressed on the surface of natural killer (NK) cells. TIGIT recognizes nectin and nectin-like adhesion molecules and thus plays a critical role in the innate immune response to malignant transformation. Although the TIGIT nectin-like protein-5 (necl-5) interaction is well understood, how TIGIT engages nectin-2, a receptor that is broadly over-expressed in breast and ovarian cancer, remains unknown. Here, we show that TIGIT bound to the immunoglobulin domain of nectin-2 that is most distal from the membrane with an affinity of 6 μm, which was moderately lower than the affinity observed for the TIGITecl-5 interaction (3.2 μm). The TIGITectin-2 binding disrupted pre-assembled nectin-2 oligomers, suggesting that receptor-ligand and ligand-ligand associations are mutually exclusive events. Indeed, the crystal structure of TIGIT bound to the first immunoglobulin domain of nectin-2 indicated that the receptor and ligand dock using the same molecular surface and a conserved “lock and key” binding motifs previously observed to mediate nectinectin homotypic interactions as well as TIGITecl-5 recognition. Using a mutagenesis approach, we dissected the energetic basis for the TIGITectin-2 interaction and revealed that an “aromatic key” of nectin-2 is critical for this interaction, whereas variations in the lock were tolerated. Moreover, we found that the C-C′ loop of the ligand dictates the TIGIT binding hierarchy. Altogether, these findings broaden our understanding of nectinectin receptor interactions and have implications for better understanding the molecular basis for autoimmune disease and cancer.