NKP44, A NOVEL TRIGGERING SURFACE-MOLECULE SPECIFICALLY EXPRESSED BY ACTIVATED NATURAL-KILLER-CELLS, IS INVOLVED IN NONMAJOR HISTOCOMPATIBILITY COMPLEX-RESTRICTED TUMOR-CELL LYSIS

After culture in interleukin (IL)-2, natural killer (NK) cells acquire an increased capability of mediating non-major histocompatibility com plex (MHC)-restricted tumor cell lysis. This may reflect, at least in part, the de novo expression by NK cells of triggering receptors invol ved in cytolysis. In this study we identified a novel 44-kD surface mo lecule (NKp44) that is absent in freshly isolated peripheral blood lym phocytes but is progressively expressed by all NK cells in vitro after culture in IL-2. Different from other markers of cell activation such as CD69 or VLA.2, NKp44 is absent in activated T lymphocytes or T cel l clones. Since NKp44 was not detected in any of the other cell lineag es analyzed, it appears as the first marker specific for activated hum an NK cells. Monoclonal antibody (mAb)-mediated cross-linking of NKp44 in cloned NK cells resulted in strong activation of target cell lysis in a redirected killing assay. This data indicated that NKp44 can med iate triggering of NK cell cytotoxicity. mAb-mediated masking of NKp44 resulted in partial inhibition of cytolytic activity against certain (Fc gamma R-negative) NK-susceptible target cells. This inhibition was greatly increased by the simultaneous masking of p46, another recentl y identified NK-specific triggering surface molecule. These data stron gly suggest that NKp44 functions as a triggering receptor selectively expressed by activated NK cells that, together with p46, may be involv ed in the process of non-MHC-restricted lysis. Finally, we show that p 46 and NKp44 are coupled to the intracytoplasmic transduction machiner y via the association with CD3 zeta or KARAP/DAP12, respectively; thes e associated molecules are tyrosine phosphorylated upon NK cell stimul ation.