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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.
 Previous Article | Next Article 
Submitted November 8, 2004
Accepted February 27, 2005
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
Department of Immunology, Juntendo University School of Medicine, Tokyo, Japan; Department of Obstetric and Genecology, Juntendo University School of Medicine, Tokyo, Japan
Department of Immunology, Juntendo University School of Medicine, Tokyo, Japan
Cancer Immunology Program, Sir Donald and Lady Trescowthick Laboratories, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia
Department of Microbiology and Immunology, and the Cancer Research Institute, University of California San Francisco, San Francisco, CA, USA
Pharmacology Division, National Cancer Center Research Institute, Tokyo, Japan
Department of Immunology, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Tokyo, Japan
Division of Developmental Immunology, La Jolla Institute for Allergy and Immunology, San Diego, CA, USA
Department of Molecular and Cell Biology and Cancer Research Laboratory, University of California, Berkeley, CA, USA
Department of Obstetric and Genecology, Juntendo University School of Medicine, Tokyo, Japan
* Corresponding author; email: ktakeda{at}med.juntendo.ac.jp.
Activation of invariant NKT (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 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. TCR and CD28 were re-expressed more rapidly than the inhibitory NK cell receptors, CD94/NKG2A and Ly49, temporally rendering the primed iNKT cells hyper-reactive to ligand re-stimulation. Interestingly, -GalCer was inferior to OCH in priming iNKT cells for subsequent re-stimulation, because -GalCer-induced IFN- up-regulated Qa-1b expression and Qa-1b in tern inhibited iNKT cell activity via its interaction with 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 CD94/NKG2A inhibitory pathway in clinical applications.
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