Cutting edge: A role for the adaptor protein LAT in human NK cell-mediatedcytotoxicity

Stimulation of NK cell-mediated cytotoxicity involves the coupling of proxi mal Src and Syk family protein tyrosine kinases to downstream effecters. Ho wever, the mechanisms linking these second messenger pathways are incomplet ely understood. Here, we describe a key role for the LAT (p36) adaptor prot ein in human NK cell activation. LAT is tyrosine phosphorylated upon stimul ation of NK cells through Fc gamma RIII receptors and following direct cont act with NK-sensitive target cells. This NK stimulation induces the associa tion of LAT with several phosphotyrosine-containing proteins. In addition t o the biochemical evidence showing LAT involvement in NK cell activation, a genetic model shows that LAT is required for FcR-dependent phosphorylation of phospholipase C-gamma. Furthermore, overexpression of LAT in NK cells l eads to increased Ab-dependent cell-mediated cytotoxicity and "natural cyto toxicity," thus demonstrating a functional role for LAT in NK cells. These data suggest that LAT is an important adaptor protein for the regulation of human NK cell-mediated cytotoxicity.