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.
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.
Ito
Hiroyasu
H
Department of Informative Clinical Medicine, Gifu University Graduate School of Medicine, 1-1 Yanagido, Gifu 501-1194, Japan. hito@gifu-u.ac.jp
Ando
Kazuki
K
Ishikawa
Tetsuya
T
Nakayama
Toshinori
T
Taniguchi
Masaru
M
Saito
Kuniaki
K
Imawari
Michio
M
Moriwaki
Hisataka
H
Yokochi
Takashi
T
Kakumu
Shinichi
S
Seishima
Mitsuru
M
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
D000956:Antigens, Viral; D005699:Galactosylceramides; C493154:alpha-galactosylceramide