NKp44, a novel triggering surface molecule specifically expressed by activated natural killer cells, is involved in non-major 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 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 (FcgammaR-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 CD3zeta or KARAP/DAP12, respectively; these associated molecules are tyrosine phosphorylated upon NK cell stimulation.
Vitale
M
M
Istituto Nazionale per la Ricerca sul Cancro and Centro Biotecnologie Avanzate, 16132 Genova, Italy.
Bottino
C
C
Sivori
S
S
Sanseverino
L
L
Castriconi
R
R
Marcenaro
E
E
Augugliaro
R
R
Moretta
L
L
Moretta
A
A
D015415:Biomarkers; D002478:Cells, Cultured; D003602:Cytotoxicity, Immunologic; D005434:Flow Cytometry; D006801:Humans; D007376:Interleukin-2 / Q000494:pharmacology; D007694:Killer Cells, Natural / Q000187:drug effects / Q000276:immunology*; D015778:Minor Histocompatibility Antigens / Q000276:immunology*; D055627:Natural Cytotoxicity Triggering Receptor 1; D055629:Natural Cytotoxicity Triggering Receptor 2; D011971:Receptors, Immunologic / Q000276:immunology / Q000302:isolation & purification*; D015398:Signal Transduction
D015415:Biomarkers; D007376:Interleukin-2; D015778:Minor Histocompatibility Antigens; C112260:NCR1 protein, human; C112837:NCR2 protein, human; D055627:Natural Cytotoxicity Triggering Receptor 1; D055629:Natural Cytotoxicity Triggering Receptor 2; D011971:Receptors, Immunologic