The interaction of TIGIT with PVR and PVRL2 inhibits human NK cell cytotoxicity

TLDR

NK cell cytotoxicity is regulated by numerous inhibitory and activating receptors, many of which bind MHC class I, and the newly identified TIGIT receptor binds PVR and related ligands to dampen T cell activity via dendritic cell modulation. All human NK cells express TIGIT, which binds PVR and PVRL2 but not PVRL3, and directly suppresses NK cytotoxicity through its ITIM, thereby reducing tumor cell killing while sparing normal cells and acting as an alternative self‑recognition pathway.

Abstract

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