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PMID: 11015434 Published · ppublish English Journal Article Research Support, U.S. Gov't, P.H.S.

Natural killer T cell activation inhibits hepatitis B virus replication in vivo.

The Journal of experimental medicine ·Vol. 192 ·No. 7 ·2000-10-02 ·Pages 921-30

Kakimi K, Guidotti LG, Koezuka Y, Chisari FV

Abstract

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)-gamma 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 alpha-galactosylceramide (alpha-GalCer), a glycolipid antigen presented to Valpha14(+)NK1.1(+) T cells by the nonclassical major histocompatibility complex class I-like molecule CD1d. Within 24 h of alpha-GalCer injection, IFN-gamma and IFN-alpha/beta 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 alpha-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 alpha-GalCer was inhibited in mice that are genetically deficient for either IFN-gamma or the IFN-alpha/beta receptor, indicating that most of the antiviral activity of alpha-GalCer is mediated by these cytokines. Based on these results, we conclude that alpha-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.

MeSH Terms
Animals Antiviral Agents/administration & dosage,immunology CD4-Positive T-Lymphocytes/immunology CD8-Positive T-Lymphocytes/immunology Dose-Response Relationship, Drug Female Galactosylceramides/administration & dosage,immunology Hepatitis B virus/drug effects,genetics,immunology,physiology Humans Killer Cells, Natural/drug effects,immunology Lymphocyte Activation/drug effects,immunology Male Mice Mice, Inbred BALB C Mice, Inbred C57BL Mice, Transgenic Time Factors Virus Replication/drug effects,immunology
Chemicals
Antiviral Agents Galactosylceramides
Authors & Affiliations
4 authors, click to expand affiliations / ORCID
Kakimi K
Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, California 92037, USA.
Guidotti L G
Koezuka Y
Chisari F V
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Article Info
Journal
The Journal of experimental medicine
Abbr.
J Exp Med
ISSN
0022-1007
DOI
10.1084/jem.192.7.921
Published
2000-10-02
Pages
921-30
Language
English
Region
United States
NLM ID
2985109R
PMCID
PMC2193313
Subset
IM
Grants
NCI NIH HHS · CA40489 · United States
NIAID NIH HHS · AI40696 · United States
External Links
PubMed source DOI: 10.1084/jem.192.7.921 PMC Full Text View journal details
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