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* Department of Immunology, Niigata University School of Medicine, Niigata, Japan;
Department of Immunology and
Department of Obstetric and Gynecology, Juntendo University School of Medicine, Tokyo, Japan;
Cancer Immunology Program, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia;
¶ Department of Molecular and Cell Biology and Cancer Research Laboratory, University of California, Berkeley, CA 94720;
|| Pharmacology Division, National Cancer Center Research Institute, Tokyo, Japan,
# Division of Developmental Immunology, La Jolla Institute for Allergy and Immunology, San Diego, CA 92121
Activation of invariant NKT (iNKT) cells in the liver is generally regarded as the critical step for Con A-induced hepatitis, and the role of NK cell receptors for iNKT cell activation is still controversial. In this study we show that blockade of the NKG2A-mediated inhibitory signal with antagonistic anti-NKG2A/C/E mAb (20d5) aggravated Con A-induced hepatitis in wild-type, Fas ligand (FasL)-mutant gld, and IL-4-deficient mice even with NK cell and CD8 T cell depletion, but not in perforin-, IFN-
-, or IFN-- and perforin-deficient mice. Consistently, 20d5 pretreatment augmented serum IFN- levels and perforin-dependent cytotoxicity of liver mononuclear cells following Con A injection, but not their FasL/Fas-dependent cytotoxicity. However, blockade of NKG2A-mediated signals during the cytotoxicity effector phase did not augment cytotoxic activity. Activated iNKT cells promptly disappeared after Con A injection, whereas NK1– iNKT cells, which preferentially expressed CD94/NKG2A, predominantly remained in the liver. Pretreatment with 20d5 appeared to facilitate disappearance of iNKT cells, particularly NK1– iNKT cells. Moreover, Con A-induced and 
-galactosylceramide-induced hepatic injury was very severe in CD94/NKG2A-deficient DBA/2J mice compared with CD94/NKG2A-intact DBA/2JJcl mice. Overall, these results indicated that a NKG2A-mediated signal negatively regulates iNKT cell activation and hepatic injury.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported by the Ministry of Education, Science, and Culture, Japan, a National Health and Medical Research Council of Australia Program Grant, the Research Fellowship, and a Cancer Council of Victoria Project Grant.
2 T.K., K.T., and H.K. contributed equally to this work.
3 Address correspondence and reprint requests to Dr. Kazuyoshi Takeda, Department of Immunology, Juntendo University School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421, Japan. E-mail address: ktakeda{at}juntendo.ac.jp
4 Abbreviations used in this paper: iNKT, invariant natural killer T cell; ALT, alanine aminotransferase; ASGM-1, asialo GM1; AST, aspartate aminotransferase; B6, C57BL/6 (mice); CMA, concanamycin A; FasL, Fas ligand; -GalCer, -galactosylceramide; MNC, mononuclear cell; WT, wild type.
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