Published online 2 October 2000.
© The Rockefeller University Press, 0022-1007/2000/10/921/ $5.00
The Journal of Experimental Medicine, Volume 192, Number 7, October 2, 2000 921-930
Natural Killer T Cell Activation Inhibits Hepatitis B Virus Replication in Vivo
Kazuhiro Kakimia,
Luca G. Guidottia,
Yasuhiko Koezukab, and
Francis V. Chisaria,b
a Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, California 92037
b Pharmaceutical Research Laboratory, Kirin Brewery Company, Limited, Takasaki-shi, Gunma 370-12, Japan
The Scripps Research Institute, 10550 North Torrey Pines Rd., La Jolla, CA 92037.858-784-2160858-784-8228
We have previously reported that hepatitis B virus (HBV)–specific CD8+ cytotoxic T lymphocytes and CD4+ helper T lymphocytes can inhibit HBV replication in the liver of HBV transgenic mice by secreting interferon (IFN)-
when they recognize viral antigen. To determine whether an activated innate immune system can also inhibit HBV replication, in this study we activated natural killer T (NKT) cells in the liver of HBV transgenic mice by a single injection of
-galactosylceramide (
-GalCer), a glycolipid antigen presented to V
14+NK1.1+ T cells by the nonclassical major histocompatibility complex class I–like molecule CD1d. Within 24 h of
-GalCer injection, IFN-
and IFN-
/β were detected in the liver of HBV transgenic mice and HBV replication was abolished. Both of these events were temporally associated with the rapid disappearance of NKT cells from the liver, presumably reflecting activation-induced cell death, and by the recruitment of activated NK cells into the organ. In addition, prior antibody-mediated depletion of CD4+ and CD8+ T cells from the mice did not diminish the ability of
-GalCer to trigger the disappearance of HBV from the liver, indicating that conventional T cells were not downstream mediators of this effect. Finally, the antiviral effect of
-GalCer was inhibited in mice that are genetically deficient for either IFN-
or the IFN-
/β receptor, indicating that most of the antiviral activity of
-GalCer is mediated by these cytokines. Based on these results, we conclude that
-GalCer inhibits HBV replication by directly activating NKT cells and by secondarily activating NK cells to secrete antiviral cytokines in the liver. In view of these findings, we suggest that, if activated, the innate immune response, like the adaptive immune response, has the potential to control viral replication during natural HBV infection. In addition, the data suggest that therapeutic activation of NKT cells may represent a new strategy for the treatment of chronic HBV infection.
Key Words: natural killer T cells transgenic/knockout hepatitis B virus immunity liver
Abbreviations used in this paper:
-GalCer,
-galactosylceramide; GAPDH, glyceraldehyde 3-phosphate dehydrogenase; HBeAg, hepatitis B e antigen; HBV, hepatitis B virus; IHL, intrahepatic lymphocyte; iNOS, inducible NO synthase;
-ManCer,
-mannosylceramide; NB, Northern blot; NKT, NK T; NO, nitric oxide; Poly-I/C, poly–inosinic-polycytidylic acid; RC, relaxed circular; RPA, RNase protection assay; sALT, serum alanine aminotransferase; SB, Southern blot; SS, single stranded.
© 2000 The Rockefeller University Press

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