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Blood, 1 January 2006, Vol. 107, No. 1, pp. 159-166. Prepublished online as a Blood First Edition Paper on September 8, 2005; DOI 10.1182/blood-2005-04-1351. This Article Full Text Full Text (PDF) All Versions of this Article: 2005-04-1351v1 107/1/159    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Bryceson, Y. T. Articles by Long, E. O. Search for Related Content PubMed PubMed Citation Articles by Bryceson, Y. T. Articles by Long, E. O. Related Collections Immunobiology Signal Transduction Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  IMMUNOBIOLOGY Synergy among receptors on resting NK cells for the activation of natural cytotoxicity and cytokine secretion Yenan T. Bryceson, Michael E. March, Hans-Gustaf Ljunggren, and Eric O. Long From the Laboratory of Immunogenetics, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, MD; and the Center for Infectious Medicine, Department of Medicine, Karolinska Institute, Karolinska University Hospital Huddinge, Stockholm, Sweden. Freshly isolated, resting natural killer (NK) cells are generally less lytic against target cells than in vitro interleukin 2 (IL-2)-activated NK cells. To investigate the basis for this difference, the contribution of several receptors to activation of human NK cells was examined. Target-cell lysis by IL-2-activated NK cells in a redirected, antibody-dependent cytotoxicity assay was triggered by a number of receptors. In contrast, cytotoxicity by resting NK cells was induced only by CD16, and not by NKp46, NKG2D, 2B4 (CD244), DNAM-1 (CD226), or CD2. Calcium flux in resting NK cells was induced with antibodies to CD16 and, to a weaker extent, antibodies to NKp46 and 2B4. Although NKp46 did not enhance CD16-mediated calcium flux, it synergized with all other receptors. 2B4 synergized with 3 other receptors, NKG2D and DNAM-1 each synergized with 2 other receptors, and CD2 synergized with NKp46 only. Resting NK cells were induced to secrete tumor necrosis factor (TNF-) and interferon (IFN-), and to kill target cells by engagement of specific, pair-wise combinations of receptors. Therefore, natural cytotoxicity by resting NK cells is induced only by mutual costimulation of nonactivating receptors. 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