title: Role of Valpha14+ NKT cells in the development of Hepatitis B virus-specific CTL: activation of Valpha14+ NKT cells promotes the breakage of CTL tolerance.
abstract: 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.
authors.affiliation: Department of Informative Clinical Medicine, Gifu University Graduate School of Medicine, 1-1 Yanagido, Gifu 501-1194, Japan. hito@gifu-u.ac.jp
authors.forename: Hiroyasu
authors.initials: H
authors.lastname: Ito
authors.forename: Kazuki
authors.initials: K
authors.lastname: Ando
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Ishikawa
authors.forename: Toshinori
authors.initials: T
authors.lastname: Nakayama
authors.forename: Masaru
authors.initials: M
authors.lastname: Taniguchi
authors.forename: Kuniaki
authors.initials: K
authors.lastname: Saito
authors.forename: Michio
authors.initials: M
authors.lastname: Imawari
authors.forename: Hisataka
authors.initials: H
authors.lastname: Moriwaki
authors.forename: Takashi
authors.initials: T
authors.lastname: Yokochi
authors.forename: Shinichi
authors.initials: S
authors.lastname: Kakumu
authors.forename: Mitsuru
authors.initials: M
authors.lastname: Seishima
mesh_terms: D000818:Animals; D000956:Antigens, Viral / Q000008:administration & dosage / Q000276:immunology / Q000378:metabolism; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D005699:Galactosylceramides / Q000008:administration & dosage / Q000276:immunology / Q000378:metabolism; D019673:Genes, T-Cell Receptor alpha / Q000276:immunology*; D006509:Hepatitis B / Q000276:immunology*; D006515:Hepatitis B virus / Q000276:immunology*; D007108:Immune Tolerance / Q000276:immunology; D008213:Lymphocyte Activation; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D008822:Mice, Transgenic; D055611:Natural Killer T-Cells / Q000276:immunology*; D037182:T-Cell Antigen Receptor Specificity; D016176:T-Lymphocyte Subsets / Q000378:metabolism; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology
chemical_list: D000956:Antigens, Viral; D005699:Galactosylceramides; C493154:alpha-galactosylceramide