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Blood, 24 September 2009, Vol. 114, No. 13, pp. 2657-2666. Prepublished online as a Blood First Edition Paper on July 23, 2009; DOI 10.1182/blood-2009-01-201632. This Article Full Text Full Text (PDF) Supplemental Figures All Versions of this Article: blood-2009-01-201632v1 114/13/2657    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 Google Scholar Articles by Bryceson, Y. T. Articles by Long, E. O. PubMed PubMed Citation Articles by Bryceson, Y. T. Articles by Long, E. O. Related Collections Immunobiology Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  IMMUNOBIOLOGY Minimal requirement for induction of natural cytotoxicity and intersection of activation signals by inhibitory receptors Yenan T. Bryceson1,2, Hans-Gustaf Ljunggren2, and Eric O. Long1 1 Laboratory of Immunogenetics, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Rockville, MD; and 2 Center for Infectious Medicine, Department of Medicine, Karolinska Institutet, Karolinska University Hospital Huddinge, Stockholm, Sweden Natural killer (NK) cells provide innate control of infected and neoplastic cells. Multiple receptors have been implicated in natural cytotoxicity, but their individual contribution remains unclear. Here, we studied the activation of primary, resting human NK cells by Drosophila cells expressing ligands for receptors NKG2D, DNAM-1, 2B4, CD2, and LFA-1. Each receptor was capable of inducing inside-out signals for LFA-1, promoting adhesion, but none induced degranulation. Rather, release of cytolytic granules required synergistic activation through coengagement of receptors, shown here for NKG2D and 2B4. Although engagement of NKG2D and 2B4 was not sufficient for strong target cell lysis, collective engagement of LFA-1, NKG2D, and 2B4 defined a minimal requirement for natural cytotoxicity. Remarkably, inside-out signaling induced by each one of these receptors, including LFA-1, was inhibited by receptor CD94/NKG2A binding to HLA-E. Strong inside-out signals induced by the combination of NKG2D and 2B4 or by CD16 could overcome CD94/NKG2A inhibition. In contrast, degranulation induced by these receptors was still subject to inhibition by CD94/NKG2A. These results reveal multiple layers in the activation pathway for natural cytotoxicity and that steps as distinct as inside-out signaling to LFA-1 and signals for granule release are sensitive to inhibition by CD94/NKG2A. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: S. M. Wood, M. Meeths, S. C. C. Chiang, A. G. Bechensteen, J. J. Boelens, C. Heilmann, H. Horiuchi, S. Rosthoj, O. Rutynowska, J. Winiarski, et al. Different NK cell-activating receptors preferentially recruit Rab27a or Munc13-4 to perforin-containing granules for cytotoxicity Blood, November 5, 2009; 114(19): 4117 - 4127. [Abstract] [Full Text] [PDF]

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