The Journal of Experimental Medicine
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© The Rockefeller University Press, 0022-1007/1998/6/2065/ $5.00
The Journal of Experimental Medicine, Volume 187, Number 12, June 15, 1998 2065-2072

Articles

NKp44, a Novel Triggering Surface Molecule Specifically Expressed by Activated Natural Killer Cells, Is Involved in Non–Major Histocompatibility Complex–restricted Tumor Cell Lysis

Massimo Vitale*, Cristina Bottino*, Simona Sivori{ddagger}, Lorenza Sanseverino{ddagger}, Roberta Castriconi{ddagger}, Emanuela Marcenaro{ddagger}, Raffaella Augugliaro{ddagger}, Lorenzo Moretta{ddagger}, and Alessandro Moretta{ddagger}

From the * Istituto Nazionale per la Ricerca sul Cancro and Centro Biotecnologie Avanzate, 16132 Genova, Italy; and the {ddagger} Dipartimento di Medicina Sperimentale, Università degli Studi di Genova, 16132 Genova, Italy

After culture in interleukin (IL)-2, natural killer (NK) cells acquire an increased capability of mediating non–major histocompatibility complex (MHC)–restricted tumor cell lysis. This may reflect, at least in part, the de novo expression by NK cells of triggering receptors involved in cytolysis. In this study we identified a novel 44-kD surface molecule (NKp44) that is absent in freshly isolated peripheral blood lymphocytes 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 cell clones. Since NKp44 was not detected in any of the other cell lineages analyzed, it appears as the first marker specific for activated human 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 mediate 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 recently identified NK-specific triggering surface molecule. These data strongly suggest that NKp44 functions as a triggering receptor selectively expressed by activated NK cells that, together with p46, may be involved in the process of non-MHC-restricted lysis. Finally, we show that p46 and NKp44 are coupled to the intracytoplasmic transduction machinery via the association with CD3{zeta} or KARAP/DAP12, respectively; these associated molecules are tyrosine phosphorylated upon NK cell stimulation.

Key Words: natural killer cells • cell-mediated cytotoxicity • activating receptors • subset-specific markers • tumor target cells

Address correspondence to Lorenzo Moretta, Centro Biotecnologie Avanzate, Largo R. Benzi 10, 16132 Genova, Italy. Phone: 39-10-57-37-217; FAX: 39-10-35-41-23; E-mail: miriello{at}sirio.cba.unige.it


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