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Attenuates NK Cell-Dependent Liver Injury Triggered by Liver NKT Cell Activation1
* Department of Physiology and Immunology, Medical Faculty, University of Rijeka, Rijeka, Croatia;
Gesellschaft für Biotechnologische Forschung, Braunschweig, Germany; and Departments of
Medical Microbiology and Immunology and
Pathology, University of Ulm, Ulm, Germany
Dendritic cell (DC)-dependent activation of liver NKT cells
triggered by a single i.v. injection of a low dose (10–100 ng/mouse)
of 
-galactosyl ceramide (GalCer) into mice induces liver injury.
This response is particularly evident in HBs-tg B6 mice that express a
transgene-encoded hepatitis B surface Ag in the liver. Liver injury
following GalCer injection is suppressed in mice depleted of NK
cells, indicating that NK cells play a role in NK T cell-initiated
liver injury. In vitro, liver NKT cells provide a CD80/86-dependent
signal to GalCer-pulsed liver DC to release IL-12 p70 that
stimulates the IFN-
response of NKT and NK cells. Adoptive transfer
of NKT cell-activated liver DC into the liver of nontreated, normal
(immunocompetent), or immunodeficient (RAG-/- or
HBs-tg/RAG-/-) hosts via the portal vein elicited IFN-
responses of liver NK cells in situ. IFN-
down-regulates the
pathogenic IL-12/IFN- cytokine cascade triggered by NKT cell/DC/NK
cell interactions in the liver. Pretreating liver DC in vitro with
IFN- suppressed their IL-12 (but not IL-10) release in response to
CD40 ligation or specific (GalCer-dependent) interaction with liver
NKT cells and down-regulated the IFN- response of the specifically
activated liver NKT cells. In vivo, IFN- attenuated the NKT
cell-triggered induction of liver immunopathology. This study
identifies interacting subsets of the hepatic innate immune system (and
cytokines that up- and down-regulate these interactions) activated
early in immune-mediated liver pathology.
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