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Blood, 1 April 2008, Vol. 111, No. 7, pp. 3571-3578. Prepublished online as a Blood First Edition Paper on January 15, 2008; DOI 10.1182/blood-2007-07-100057. This Article Full Text (PDF) Supplemental Figure All Versions of this Article: blood-2007-07-100057v1 111/7/3571    most recent Alert me when this article is cited Alert me if a correction is posted 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 Coudert, J. D Articles by Held, W. Search for Related Content PubMed PubMed Citation Articles by Coudert, J. D Articles by Held, W. Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted July 6, 2007 Accepted January 6, 2008 Sustained NKG2D engagement induces cross-tolerance of multiple distinct NK cell activation pathways Jerome D Coudert, Leonardo Scarpellino, Frederic Gros, Eric Vivier, and Werner Held* Ludwig Institute for Cancer Research, Lausanne Branch and University of Lausanne, Epalinges, Switzerland Centre d'Immunologie de Marseille-Luminy, Universite de la Meditarranee, Campus de Luminy, Marseille, France * Corresponding author; email: wheld{at}isrec.unil.ch. NKG2D is a multi-subunit activation receptor, which allows NK cells to detect and eliminate stressed, infected and transformed host cells. However, the chronic exposure of NK cells to cell-bound NKG2D ligands has been shown to impair NKG2D function both in vitro and in vivo. Here we have tested whether continuous NKG2D engagement selectively impacted NKG2D function or whether heterologous NK cell activation pathways were also affected. We find that sustained NKG2D engagement induces cross-tolerization of several unrelated NK cell activation receptors. We show that receptors that activate NK cells via the DAP12/KARAP and DAP10 signaling adaptors, such as murine NKG2D and Ly49D, cross-tolerize preferentially NK cell activation pathways that function independent of DAP10/12, such as antibody-dependent cell mediated cytotoxicity and missing self-recognition. Conversely, DAP10/12-independent pathways are unable to cross-tolerize unrelated NK cell activation receptors such as NKG2D or Ly49D. These data define a class of NK cell activation receptors that can tolerize mature NK cells. The reversible suppression of the NK cells' cytolytic function likely reduces the NK cells' efficacy to control endogenous and exogenous stress yet may be needed to limit tissue damage. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: M. Hedlund, A.-C. Stenqvist, O. Nagaeva, L. Kjellberg, M. Wulff, V. Baranov, and L. Mincheva-Nilsson Human Placenta Expresses and Secretes NKG2D Ligands via Exosomes that Down-Modulate the Cognate Receptor Expression: Evidence for Immunosuppressive Function J. Immunol., July 1, 2009; 183(1): 340 - 351. [Abstract] [Full Text] [PDF] M. T. Orr, J. C. Sun, D. G.T. Hesslein, H. Arase, J. H. Phillips, T. Takai, and L. L. Lanier Ly49H signaling through DAP10 is essential for optimal natural killer cell responses to mouse cytomegalovirus infection J. Exp. Med., April 13, 2009; 206(4): 807 - 817. [Abstract] [Full Text] [PDF] M. Inui, Y. Kikuchi, N. Aoki, S. Endo, T. Maeda, A. Sugahara-Tobinai, S. Fujimura, A. Nakamura, A. Kumanogoh, M. Colonna, et al. Signal adaptor DAP10 associates with MDL-1 and triggers osteoclastogenesis in cooperation with DAP12 PNAS, March 24, 2009; 106(12): 4816 - 4821. [Abstract] [Full Text] [PDF] H. Guo, A. Samarakoon, B. Vanhaesebroeck, and S. Malarkannan The p110{delta} of PI3K plays a critical role in NK cell terminal maturation and cytokine/chemokine generation J. Exp. Med., September 29, 2008; 205(10): 2419 - 2435. [Abstract] [Full Text] [PDF]

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