SEARCH:   Advanced

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] Q. Tang, B. Grzywacz, H. Wang, N. Kataria, Q. Cao, J. E. Wagner, B. R. Blazar, J. S. Miller, and M. R. Verneris Umbilical Cord Blood T Cells Express Multiple Natural Cytotoxicity Receptors after IL-15 Stimulation, but Only NKp30 Is Functional J. Immunol., October 1, 2008; 181(7): 4507 - 4515. [Abstract] [Full Text] [PDF] R. Nishimura, J. Baker, A. Beilhack, R. Zeiser, J. A. Olson, E. I. Sega, M. Karimi, and R. S. Negrin In vivo trafficking and survival of cytokine-induced killer cells resulting in minimal GVHD with retention of antitumor activity Blood, September 15, 2008; 112(6): 2563 - 2574. [Abstract] [Full Text] [PDF] K. Kraetzel, B. Stoelcker, G. Eissner, G. Multhoff, M. Pfeifer, E. Holler, and C. Schulz NKG2D-dependent effector function of bronchial epithelium-activated alloreactive T-cells Eur. Respir. J., September 1, 2008; 32(3): 563 - 570. [Abstract] [Full Text] [PDF] W. Cao, X. Xi, Z. Wang, L. Dong, Z. Hao, L. Cui, C. Ma, and W. He Four novel ULBP splice variants are ligands for human NKG2D Int. Immunol., August 1, 2008; 20(8): 981 - 991. [Abstract] [Full Text] [PDF] D. Sangiolo, E. Martinuzzi, M. Todorovic, K. Vitaggio, A. Vallario, N. Jordaney, F. Carnevale-Schianca, A. Capaldi, M. Geuna, L. Casorzo, et al. Alloreactivity and anti-tumor activity segregate within two distinct subsets of cytokine-induced killer (CIK) cells: implications for their infusion across major HLA barriers Int. Immunol., July 1, 2008; 20(7): 841 - 848. [Abstract] [Full Text] [PDF] A. Clayton, J. P. Mitchell, J. Court, S. Linnane, M. D. Mason, and Z. Tabi Human Tumor-Derived Exosomes Down-Modulate NKG2D Expression J. Immunol., June 1, 2008; 180(11): 7249 - 7258. [Abstract] [Full Text] [PDF] M. Vales-Gomez, S. E. Chisholm, R. L. Cassady-Cain, P. Roda-Navarro, and H. T. Reyburn Selective Induction of Expression of a Ligand for the NKG2D Receptor by Proteasome Inhibitors Cancer Res., March 1, 2008; 68(5): 1546 - 1554. [Abstract] [Full Text] [PDF] A. I. Marusina, S. J. Burgess, I. Pathmanathan, F. Borrego, and J. E. Coligan Regulation of Human DAP10 Gene Expression in NK and T Cells by Ap-1 Transcription Factors J. Immunol., January 1, 2008; 180(1): 409 - 417. [Abstract] [Full Text] [PDF] H. Zhang, K. M. Snyder, M. M. Suhoski, M. V. Maus, V. Kapoor, C. H. June, and C. L. Mackall 4-1BB Is Superior to CD28 Costimulation for Generating CD8+ Cytotoxic Lymphocytes for Adoptive Immunotherapy J. Immunol., October 1, 2007; 179(7): 4910 - 4918. [Abstract] [Full Text] [PDF] B. K. Choi, Y. H. Kim, W. J. Kang, S. K. Lee, K. H. Kim, S. M. Shin, W. M. Yokoyama, T. Y. Kim, and B. S. Kwon Mechanisms Involved in Synergistic Anticancer Immunity of Anti-4-1BB and Anti-CD4 Therapy Cancer Res., September 15, 2007; 67(18): 8891 - 8899. [Abstract] [Full Text] [PDF] H. Wang, B. Grzywacz, D. Sukovich, V. McCullar, Q. Cao, A. B. Lee, B. R. Blazar, D. N. Cornfield, J. S. Miller, and M. R. Verneris The unexpected effect of cyclosporin A on CD56+CD16 and CD56+CD16+ natural killer cell subpopulations Blood, September 1, 2007; 110(5): 1530 - 1539. [Abstract] [Full Text] [PDF] J. N. Beilke and R. G. Gill Frontiers in Nephrology: The Varied Faces of Natural Killer Cells in Transplantation Contributions to Both Allograft Immunity and Tolerance J. Am. Soc. Nephrol., August 1, 2007; 18(8): 2262 - 2267. [Abstract] [Full Text] [PDF] M. Introna, G. Borleri, E. Conti, M. Franceschetti, A. M. Barbui, R. Broady, E. Dander, G. Gaipa, G. D'Amico, E. Biagi, et al. Repeated infusions of donor-derived cytokine-induced killer cells in patients relapsing after allogeneic stem cell transplantation: a phase I study Haematologica, July 1, 2007; 92(7): 952 - 959. [Abstract] [Full Text] [PDF] W. Cao, X. Xi, Z. Hao, W. Li, Y. Kong, L. Cui, C. Ma, D. Ba, and W. He RAET1E2, a Soluble Isoform of the UL16-binding Protein RAET1E Produced by Tumor Cells, Inhibits NKG2D-mediated NK Cytotoxicity J. Biol. Chem., June 29, 2007; 282(26): 18922 - 18928. [Abstract] [Full Text] [PDF] P. S. Joshi, J.-Q. Liu, Y. Wang, X. Chang, J. Richards, E. Assarsson, F.-D. Shi, H.-G. Ljunggren, and X.-F. Bai Cytokine-induced killer T cells kill immature dendritic cells by TCR-independent and perforin-dependent mechanisms J. Leukoc. Biol., December 1, 2006; 80(6): 1345 - 1353. [Abstract] [Full Text] [PDF] S. H. Thorne, R. S. Negrin, and C. H. Contag Synergistic antitumor effects of immune cell-viral biotherapy. Science, March 24, 2006; 311(5768): 1780 - 1784. [Abstract] [Full Text] [PDF] J. K. Chan, C. A. Hamilton, M. K. Cheung, M. Karimi, J. Baker, J. M. Gall, S. Schulz, S. H. Thorne, N. N. Teng, C. H. Contag, et al. Enhanced killing of primary ovarian cancer by retargeting autologous cytokine-induced killer cells with bispecific antibodies: a preclinical study. Clin. Cancer Res., March 15, 2006; 12(6): 1859 - 1867. [Abstract] [Full Text] [PDF] T. Baba, A. Ishizu, S. Iwasaki, A. Suzuki, U. Tomaru, H. Ikeda, T. Yoshiki, and M. Kasahara CD4+/CD8+ macrophages infiltrating at inflammatory sites: a population of monocytes/macrophages with a cytotoxic phenotype Blood, March 1, 2006; 107(5): 2004 - 2012. [Abstract] [Full Text] [PDF] M. Karimi, T. M. Cao, J. A. Baker, M. R. Verneris, L. Soares, and R. S. Negrin Silencing Human NKG2D, DAP10, and DAP12 Reduces Cytotoxicity of Activated CD8+ T Cells and NK Cells J. Immunol., December 15, 2005; 175(12): 7819 - 7828. [Abstract] [Full Text] [PDF] M. A. Markiewicz, L. N. Carayannopoulos, O. V. Naidenko, K. Matsui, W. R. Burack, E. L. Wise, D. H. Fremont, P. M. Allen, W. M. Yokoyama, M. Colonna, et al. Costimulation through NKG2D Enhances Murine CD8+ CTL Function: Similarities and Differences between NKG2D and CD28 Costimulation J. Immunol., September 1, 2005; 175(5): 2825 - 2833. [Abstract] [Full Text] [PDF] B. Rincon-Orozco, V. Kunzmann, P. Wrobel, D. Kabelitz, A. Steinle, and T. Herrmann Activation of V{gamma}9V{delta}2 T Cells by NKG2D J. Immunol., August 15, 2005; 175(4): 2144 - 2151. [Abstract] [Full Text] [PDF] L. I. R. Ehrlich, K. Ogasawara, J. A. Hamerman, R. Takaki, A. Zingoni, J. P. Allison, and L. L. Lanier Engagement of NKG2D by Cognate Ligand or Antibody Alone Is Insufficient to Mediate Costimulation of Human and Mouse CD8+ T Cells J. Immunol., February 15, 2005; 174(4): 1922 - 1931. [Abstract] [Full Text] [PDF]

	Copyright © 2004 by American Society of Hematology         Online ISSN: 1528-0020