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Blood, 1 July 2005, Vol. 106, No. 1, pp. 184-192. Prepublished online as a Blood First Edition Paper on March 3, 2005; DOI 10.1182/blood-2004-11-4257. This Article Full Text Full Text (PDF) All Versions of this Article: 2004-11-4257v1 106/1/184    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 Ota, T. Articles by Okumura, K. Search for Related Content PubMed PubMed Citation Articles by Ota, T. Articles by Okumura, K. Related Collections Immunobiology Immunotherapy Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  IMMUNOBIOLOGY IFN-–mediated negative feedback regulation of NKT-cell function by CD94/NKG2 Tsuyoshi Ota, Kazuyoshi Takeda, Hisaya Akiba, Yoshihiro Hayakawa, Kouetsu Ogasawara, Yoshinori Ikarashi, Sachiko Miyake, Hiro Wakasugi, Takashi Yamamura, Mitchell Kronenberg, David H. Raulet, Katsuyuki Kinoshita, Hideo Yagita, Mark J. Smyth, and Ko Okumura From the Departments of Immunology, and Obstetrics and Gynecology, Juntendo University School of Medicine, Tokyo, Japan; Cancer Immunology Program, Sir Donald and Lady Trescowthick Laboratories, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia; Department of Microbiology and Immunology and the Cancer Research Institute, University of California San Francisco, San Francisco, CA; Pharmacology Division, National Cancer Center Research Institute, Tokyo, Japan; Department of Immunology, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Kodaira, Tokyo, Japan; Division of Developmental Immunology, La Jolla Institute for Allergy and Immunology, San Diego, CA; and Department of Molecular and Cell Biology and Cancer Research Laboratory, University of California, Berkeley, CA. Activation of invariant natural killer T (iNKT) cells with CD1d-restricted T-cell receptor (TCR) ligands is a powerful means to modulate various immune responses. However, the iNKT-cell response is of limited duration and iNKT cells appear refractory to secondary stimulation. Here we show that the CD94/NKG2A inhibitory receptor plays a critical role in down-regulating iNKT-cell responses. Both TCR and NK-cell receptors expressed by iNKT cells were rapidly down-modulated by priming with -galactosylceramide (-GalCer) or its analog OCH [(2S,3S,4R)-1-O-(-D-galactopyranosyl)-N-tetracosanoyl-2-amino-1,3,4-nonanetriol)]. TCR and CD28 were re-expressed more rapidly than the inhibitory NK-cell receptors CD94/NKG2A and Ly49, temporally rendering the primed iNKT cells hyperreactive to ligand restimulation. Of interest, -GalCer was inferior to OCH in priming iNKT cells for subsequent restimulation because -GalCer–induced interferon (IFN-) up-regulated Qa-1b expression and Qa-1b in turn inhibited iNKT-cell activity via its interaction with the inhibitory CD94/NKG2A receptor. Blockade of the CD94/NKG2–Qa-1b interaction markedly augmented recall and primary responses of iNKT cells. This is the first report to show the critical role for NK-cell receptors in controlling iNKT-cell responses and provides a novel strategy to augment the therapeutic effect of iNKT cells by priming with OCH or blocking of the CD94/NKG2A inhibitory pathway in clinical applications. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: M. Biburger and G. Tiegs Activation-induced NKT cell hyporesponsiveness protects from {alpha}-galactosylceramide hepatitis and is independent of active transregulatory factors J. Leukoc. 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Sardinha, R. M. Elias, T. Mosca, K. R. B. Bastos, C. R. F. Marinho, M. R. D'Imperio Lima, and J. M. Alvarez Contribution of NK, NK T, {gamma}{delta} T, and {alpha}{beta} T Cells to the Gamma Interferon Response Required for Liver Protection against Trypanosoma cruzi Infect. Immun., April 1, 2006; 74(4): 2031 - 2042. [Abstract] [Full Text] [PDF] A. P. Uldrich, N. Y. Crowe, K. Kyparissoudis, D. G. Pellicci, Y. Zhan, A. M. Lew, P. Bouillet, A. Strasser, M. J. Smyth, and D. I. Godfrey NKT Cell Stimulation with Glycolipid Antigen In Vivo: Costimulation-Dependent Expansion, Bim-Dependent Contraction, and Hyporesponsiveness to Further Antigenic Challenge J. Immunol., September 1, 2005; 175(5): 3092 - 3101. [Abstract] [Full Text] [PDF] K. Minami, Y. Yanagawa, K. Iwabuchi, N. Shinohara, T. Harabayashi, K. Nonomura, and K. Onoe Negative feedback regulation of T helper type 1 (Th1)/Th2 cytokine balance via dendritic cell and natural killer T cell interactions Blood, September 1, 2005; 106(5): 1685 - 1693. [Abstract] [Full Text] [PDF]

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