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Blood, 15 April 2004, Vol. 103, No. 8, pp. 3065-3072. Prepublished online as a Blood First Edition Paper on November 20, 2003; DOI 10.1182/blood-2003-06-2125. This Article Full Text Full Text (PDF) All Versions of this Article: 2003-06-2125v1 103/8/3065    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 Verneris, M. R. Articles by Negrin, R. S. Search for Related Content PubMed PubMed Citation Articles by Verneris, M. R. Articles by Negrin, R. S. Related Collections Immunobiology Signal Transduction Gene Expression Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  IMMUNOBIOLOGY Role of NKG2D signaling in the cytotoxicity of activated and expanded CD8+ T cells Michael R. Verneris, Mobin Karami, Jeanette Baker, Anishka Jayaswal, and Robert S. Negrin From the Division of Pediatric Blood and Marrow Diseases, University of Minnesota, Minneapolis, MN; and Department of Medicine, Division of Bone Marrow Transplantation, Stanford University, Stanford, CA. Activating and expanding T cells using T-cell receptor (TCR) cross-linking antibodies and interleukin 2 (IL-2) results in potent cytotoxic effector cells capable of recognizing a broad range of malignant cell targets, including autologous leukemic cells. The mechanism of target cell recognition has previously been unknown. Recent studies show that ligation of NKG2D on natural killer (NK) cells directly induces cytotoxicity, whereas on T cells it costimulates TCR signaling. Here we demonstrate that NKG2D expression is up-regulated upon activation and expansion of human CD8+ T cells. Antibody blocking, redirected cytolysis, and small interfering RNA (siRNA) studies using purified CD8+ T cells demonstrate that cytotoxicity against malignant target cells occurs through NKG2D-mediated recognition and signaling and not through the TCR. Activated and expanded CD8+ T cells develop cytotoxicity after 10 to 14 days of culture, coincident with the expression of the adapter protein DAP10. T cells activated and expanded in low (30 U/mL) and high (300 U/mL) concentrations of IL-2 both up-regulated NKG2D expression equally, but only cells cultured in high-dose IL-2 expressed DAP10 and were cytotoxic. Collectively these results establish that NKG2D triggering accounts for the majority of major histocompatibility complex (MHC)–unrestricted cytotoxicity of activated and expanded CD8+ T cells, likely through DAP10-mediated signaling. (Blood. 2004;103: 3065-3072) CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: C. Cerboni, M. Ardolino, A. Santoni, and A. Zingoni Detuning CD8+ T lymphocytes by down-regulation of the activating receptor NKG2D: role of NKG2D ligands released by activated T cells Blood, March 26, 2009; 113(13): 2955 - 2964. [Abstract] [Full Text] [PDF] F. Tang, Z. Chen, C. Ciszewski, M. Setty, J. Solus, M. Tretiakova, E. Ebert, J. Han, A. Lin, S. Guandalini, et al. Cytosolic PLA2 is required for CTL-mediated immunopathology of celiac disease via NKG2D and IL-15 J. Exp. Med., March 16, 2009; 206(3): 707 - 719. [Abstract] [Full Text] [PDF] D. Sangiolo, E. Martinuzzi, M. Todorovic, K. 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