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Fas Ligand Is Responsible for CXCR3 Chemokine Induction in CD4⁺ T Cell-Dependent Liver Damage¹

Michael W. Cruise^*,, John R. Lukens^*,, Aileen P. Nguyen^*, Matthew G. Lassen^*,, Stephen N. Waggoner^*, and Young S. Hahn^2,*,,

^* Beirne Carter Center for Immunology Research, Department of Microbiology, and Department of Pathology, University of Virginia, Charlottesville, VA 22908

Immune-mediated hepatic damage has been demonstrated in the pathogenesis of hepatitis C virus (HCV) and other hepatotrophic infections. Fas/Fas ligand (FasL) interaction plays a critical role in immune-mediated hepatic damage. To understand the molecular mechanism(s) of FasL-mediated liver inflammation, we examined the effect of CD4⁺ T cells expressing high levels of FasL on the initiation of hepatic damage through analysis of chemokine and chemokine receptor expression in HCV core x TCR (DO11.10) double-transgenic mice. In vivo antigenic stimulation triggers a marked influx of core-expressing Ag-specific CD4⁺ T cells into the liver of the immunized core⁺ TCR mice but not their core^– TCR littermates. Strikingly, the inflammatory process in the liver of core⁺ TCR mice was accompanied by a dramatic increase in IFN-inducible protein 10 and monokine induced by IFN- production. The intrahepatic lymphocytes were primarily CXCR3-positive and anti-CXCR3 Ab treatment abrogates migration of CXCR3⁺ lymphocytes into the liver and hepatic damage. Importantly, the blockade of Fas/FasL interaction reduces the expression of IFN-inducible protein 10 and monokine induced by IFN- and cellular infiltration into the liver. These findings suggest that activated CD4⁺ T cells with elevated FasL expression are involved in promoting liver inflammation and hepatic damage through the induction of chemokines.