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

Abstract

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 (FcγR-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 CD3ζ or KARAP/DAP12, respectively; these associated molecules are tyrosine phosphorylated upon NK cell stimulation.

Gntb-A, a Novel Sh2d1a-Associated Surface Molecule Contributing to the Inability of Natural Killer Cells to Kill Epstein-Barr Virus–Infected B Cells in X-Linked Lymphoproliferative Disease

“…NTB-A does not contain classical ITAM consensus sequence in the cytoplasmic tail. Different from various activating surface receptors but similar to 2B4 8 9 10 16, NTB-A does not associate with DAP12, CD3ζ, and FcεRIγ signal transducing polypeptides. Moreover, unlike 2B4 29, NTB-A does not associate with the LAT (not shown).…”

“…For one- or two-color cytofluorimetric analysis (FACScan™; Becton Dickinson) cells were stained with the appropriate mAbs followed by PE- or FITC-conjugated isotype-specific goat anti–mouse second reagent (Southern Biotechnology Associates, Inc. [6, 8, 9]).…”

CD56bright NK cells after hematopoietic stem cell transplantation are activated mature NK cells that expand in patients with low numbers of T cells

“…Mature NK cells cultured in the presence of cytokines express markers such as HLA-DR [8] and NKp44 [23] that were downregulated during progression of pre-NK cells to more mature developmental stages [19]. Furthermore, CD56 dim upregulate CD56 after activation by cytokines [24], downregulate CD16 after contact with target cells [25] and acquire receptors to home to lymph nodes after stimulation with IL-18 [26].…”

Identification and hormonal regulation of a novel form of NKp30 in human endometrial epithelium

“…NKp30 and NKp46 are thought to be selectively expressed in resting and activated NK cells, while NKp44 receptor is only expressed in NK cells following activation [2][3][4][5]. There are also studies reporting the expression of these receptors in non-classical NK cells, as well as hematopoietic cells of various lineages and nonhematopoietic cells, suggesting that they might not be confined solely to NK cells [6].…”