Ito Hiroyasu, Ando Kazuki, Ishikawa Tetsuya, Nakayama Toshinori, Taniguchi Masaru, Saito Kuniaki, Imawari Michio, Moriwaki Hisataka, Yokochi Takashi, Kakumu Shinichi, Seishima Mitsuru
Department of Informative Clinical Medicine, Gifu University Graduate School of Medicine, 1-1 Yanagido, Gifu 501-1194, Japan.
Int Immunol. 2008 Jul;20(7):869-79. doi: 10.1093/intimm/dxn046. Epub 2008 May 16.
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 Valpha14-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.
细胞毒性T淋巴细胞（CTL）被认为是清除包括乙型肝炎病毒（HBV）在内的急性感染中病毒的主要效应细胞。持续性HBV感染的特征是对HBV缺乏或仅有微弱的CTL反应，这被认为反映了对HBV抗原的耐受。在本研究中，我们发现α-半乳糖神经酰胺（α-GalCer），一种Vα14阳性自然杀伤T细胞（NKT细胞）的配体，能强烈增强由乙肝表面抗原（HBsAg）诱导的HBV特异性CTL的诱导和增殖。在被认为对HBV编码抗原耐受的HBsAg转基因小鼠中，单独给予HBsAg或α-GalCer未能诱导出HBsAg特异性CTL，但二者共同给予时则可诱导产生。此外，通过有限稀释分析，我们证实在用HBsAg和α-GalCer免疫的HBsAg转基因小鼠中存在HBsAg特异性CTL前体。一项使用细胞因子抗体和CD40配体的阻断实验表明，白细胞介素-2（IL-2）和CD40-CD40L相互作用通过NKT细胞激活介导了α-GalCer引起的CTL诱导增强。我们的结果可能为从持续性HBV感染患者体内清除病毒开辟一种新方法。
