Activating receptors and coreceptors involved in human natural killer cell-mediated cytolysis

Natural killer cells can discriminate between normal cells and cells that d o not express adequate amounts of major histocompatibility complex (MHC) cl ass I molecules. The discovery, both in mouse and in human, of MHC specific inhibitory receptors clarified the molecular basis of this important NK ce ll function. However, the triggering receptors responsible for positive NK cell stimulation remained elusive until recently. Some of these receptors h ave now been identified in humans, thus shedding some light on the molecula r mechanisms involved in NK cell activation during the process of natural c ytotoxicity. Three novel, NK-specific, triggering surface molecules (NKp46, NKp30, and NKp44) have been identified. They represent the first members o f a novel emerging group of receptors collectively termed natural cytotoxic ity receptors (NCR). Monoclonal antibodies (mAbs) to NCR block to differing extents the NK-mediated lysis of various tumors. Moreover, lysis of certai n tumors can be virtually abrogated by the simultaneous masking of the thre e NCRs. There is a coordinated surface expression of the three NCRs, their surface density varying in different individuals and also in the NK cells i solated from a given individual. A direct correlation exists between the su rface density of NCR and the ability of NK cells to kill various tumors. NK p46 is the only NCR involved in human NK-mediated killing of murine target cells. Accordingly, a homologue of NKp46 has been detected in mouse. Molecu lar cloning of NCR revealed novel members of the Ig superfamily displaying a low degree of similarity to each other and to known human molecules. NCRs are coupled to different signal transducing adaptor proteins, including CD 3 zeta, Fc epsilon RI gamma, and KARAP/DAP12. Another triggering NK recepto r is NKG2D. It appears to play either a complementary or a synergistic role with NCRs. Thus, the triggering of NK cells in the process of tumor cell l ysis may often depend on the concerted action of NCR and NKG2D. In some ins tances, however, it may uniquely depend upon the activity of NCR or NKG2D o nly. Strict NKG2D-dependency can be appreciated using clones that, in spite of their NCRdull phenotype, efficiently lyse certain epithelial tumors or leukemic cell lines. Other triggering surface molecules including 2B4 and t he novel NKp80 appear to function as coreceptors rather than as true recept ors. Indeed, they can induce natural cytotoxicity only when co-engaged with a triggering receptor. While an altered expression or function of NCR or N KG2D is being explored as a possible cause of immunological disorders, 2B4 dysfunction has already been associated with a severe form of immunodeficie ncy. indeed, in patients with the X-linked lymphoproliferative disease, the inability to control Epstein-Barr virus infections may be consequent to a major dysfunction of 2B4 that exerts inhibitory instead of activating funct ions.