Tumor-Induced Apoptosis of Human IL-2-Activated NK Cells: Role of Natural Cytotoxicity Receptors

We provide evidence that tumor cells can induce apoptosis of NK cells by engaging the natural cytotoxicity receptors (NCR) NKp30, NKp44, and NKp46. Indeed, the binding between NCR on NK cells and their putative ligands on tumor target cells led to NK cell apoptosis, and this event was abolished by b...

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Bibliographic Details
Published in:The Journal of immunology (1950) 2005-03, Vol.174 (5), p.2653-2660
Main Authors: Poggi, Alessandro, Massaro, Anna-Maria, Negrini, Simone, Contini, Paola, Zocchi, Maria Raffaella
Format: Article
Language:English
Subjects:
Antibodies, Monoclonal - metabolism
Apoptosis - immunology
Calcium - physiology
Caspase 3
Caspases - metabolism
Cell Communication - immunology
Cell Line, Transformed
Cells, Cultured
Clone Cells
Cytotoxicity, Immunologic
Enzyme Activation
Fas Ligand Protein
fas Receptor - physiology
Humans
Interleukin-2 - pharmacology
Killer Cells, Natural - cytology
Killer Cells, Natural - immunology
Killer Cells, Natural - metabolism
Lymphocyte Activation - immunology
Melanoma - immunology
Melanoma - pathology
Melanoma - prevention & control
Membrane Glycoproteins - biosynthesis
Membrane Glycoproteins - genetics
Membrane Glycoproteins - metabolism
Membrane Glycoproteins - physiology
Natural Cytotoxicity Triggering Receptor 1
Natural Cytotoxicity Triggering Receptor 2
Natural Cytotoxicity Triggering Receptor 3
Receptors, Immunologic - metabolism
Receptors, Immunologic - physiology
RNA, Messenger - biosynthesis
Up-Regulation - immunology
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Summary:We provide evidence that tumor cells can induce apoptosis of NK cells by engaging the natural cytotoxicity receptors (NCR) NKp30, NKp44, and NKp46. Indeed, the binding between NCR on NK cells and their putative ligands on tumor target cells led to NK cell apoptosis, and this event was abolished by blocking NCR/NCR-ligand interaction by anti-NCR-specific mAbs. The engagement of NCR induced up-regulation of Fas ligand (FasL) mRNA, FasL protein synthesis, and release. In turn, FasL interacting with Fas at NK cell surface causes NK cell suicide, as apoptosis of NK cells was inhibited by blocking FasL/Fas interaction with specific mAbs. Interestingly, NK cell apoptosis, but not killing of tumor target cells, is inhibited by cyclosporin A, suggesting that apoptosis and cytolysis are regulated by different biochemical pathways. These findings indicate that NCR are not only triggering molecules essential for antitumor activity, but also surface receptors involved in NK cell suicide.
ISSN:0022-1767
1550-6606
DOI:10.4049/jimmunol.174.5.2653