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International Immunology Advance Access originally published online on May 16, 2008
International Immunology 2008 20(7):869-879; doi:10.1093/intimm/dxn046
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© The Japanese Society for Immunology. 2008. All rights reserved. For permissions, please e-mail: journals.permissions@oxfordjournals.org

Role of V{alpha}14+ NKT cells in the development of Hepatitis B virus-specific CTL: activation of V{alpha}14+ NKT cells promotes the breakage of CTL tolerance

Hiroyasu Ito1,2,*, Kazuki Ando1,3,*, Tetsuya Ishikawa4, Toshinori Nakayama5, Masaru Taniguchi6, Kuniaki Saito1,7, Michio Imawari8, Hisataka Moriwaki9, Takashi Yokochi2, Shinichi Kakumu10 and Mitsuru Seishima1

1 Department of Informative Clinical Medicine, Gifu University Graduate School of Medicine, 1-1 Yanagido, Gifu 501-1194, Japan
2 Department of Microbiology and Immunology, Aichi Medical University, Nagakute, Aichi 480-1195, Japan
3 Goto Clinic, Gifu 503-0899, Japan
4 Cancer Immunotherapy Center, Nagoya Kyoritsu Hospital, 1-172 Hokke, Nakagawa, Nagoya 454-0933, Japan
5 Department of Immunology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan
6 RIKEN Research Center for Allergy and Immunology, RIKEN Yokohama Institute, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama City, Kanagawa 230-0045, Japan
7 Human Health Sciences, Graduate School of Medicine and Faculty of Medicine, Kyoto University, 53 Kawahara-cho, Shogoin, Sakyo, Kyoto 606-8507, Japan
8 Second Department of Internal Medicine, Showa University School of Medicine, 1-5-8 Hatanodai, Shinagawa-ku, Tokyo 142-8666, Japan
9 First Department of Internal Medicine, Gifu University Graduate School of Medicine, 1-1 Yanagido, Gifu 501-1194, Japan
10 Division of Gastroenterology, Department of Internal Medicine, Aichi Medical University, Nagakute, Aichi 480-1195, Japan

Correspondence to: H. Ito; E-mail: hito{at}gifu-u.ac.jp

CTLs are thought to be major effectors for clearing viruses in acute infections including hepatitis B virus (HBV). Persistent HBV infection is characterized by a lack of or a weak CTL response to HBV, which is thought to reflect tolerance to HBV antigens. In the present study, we found that alpha-galactosylceramide ({alpha}-GalCer), a ligand for V{alpha}14-positive NKT cells, strongly enhanced the induction and proliferation of HBV-specific CTLs by HBsAg. In HBsAg transgenic mice, which are thought to be tolerant to HBV-encoded antigens, administration of HBsAg or {alpha}-GalCer alone failed to induce HBsAg-specific CTLs, but they were induced by co-administration of both compounds. Furthermore, by limiting dilution analysis, we confirmed the existence of HBsAg-specific CTL precursors in the HBsAg transgenic mice immunized with HBsAg and {alpha}-GalCer. A blocking experiment using antibodies to cytokines and CD40 ligand showed that IL-2 and CD40–CD40L interaction mediate the enhancement of CTL induction caused by {alpha}-GalCer through NKT cell activation. Our results may open up a new method for clearing the virus from patients with persistent HBV infection.

Keywords: CTL, hepatitis B virus, NKT cell

* These authors contributed equally to this study.

Transmitting editor: H. Karasuyama

Received 10 August 2007, accepted 16 April 2008.


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