Role of Va14 super(+) NKT cells in the development of Hepatitis B virus-specific CTL: activation of Va14 super(+) NKT cells promotes the breakage of CTL tolerance

• Published in: International immunology 2008-07, Vol.20 (7), p.869-879
• Main Authors: Ito, Hiroyasu, Ando, Kazuki, Ishikawa, Tetsuya, Nakayama, Toshinori, Taniguchi, Masaru, Saito, Kuniaki, Imawari, Michio, Moriwaki, Hisataka, Yokochi, Takashi, Kakumu, Shinichi, Seishima, Mitsuru
• Format: Article
• Language: English
• Subjects: Hepatitis B virus
• ISSN: 0953-8178; 1460-2377

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 (a-GalCer), a ligand for Va14-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 a-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 a-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 a-GalCer through NKT cell activation. Our results may open up a new method for clearing the virus from patients with persistent HBV infection.