Role of NKG2D in tumor cell lysis mediated by human NK cells: cooperation with natural cytotoxicity receptors and capability of recognizing tumors ofnonepithelial origin

NKG2D is a recently described activating receptor expressed by both NK cell s and CTL. In this study we investigated the role of NKG2D in the natural c ytolysis mediated by NK cell clones. The role of NKG2D varied depending on the type of target cells analyzed. Lysis of various tumors appeared to be e xclusively natural cytotoxicity receptors (NCR) dependent. In contrast, kil ling of another group of target cells, including not only the epithelial ce ll lines HELA and IGROV-1, but also the FO-1 melanoma, the JA3 leukemia, th e Daudi Burkitt lymphoma and even normal PHA-induced lymphoblasts, involved both NCR and NKG2D. Notably, NK cell clones expressing low surface densiti es of NCR (NCRdull) could lyse these tumors in an exclusively NKG2D-depende nt fashion. Remarkably, not all of these targets expressed MICA/B, thus imp lying the existence of additional ligands recognized by NKG2D, possibly rep resented by GPI-linked molecules. Finally, we show that the engagement of d ifferent HLA class I-specific inhibitory receptors by either specific antib odies or the appropriate HLA class I ligand led to inhibition of NKG2D-medi ated NK cell triggering.