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* First Department of Oral and Maxillofacial Surgery,
Department of Oral Pathology, and
Clinical Laboratory, Kanagawa Dental College, Kanagawa, Japan;
Department of Medicine, Kitasato Institute Hospital, Tokyo, Japan; and
¶ Institute of Molecular Biotechnology of the Austrian Academy of Sciences and Department of Medical Biophysics and Immunology, Ontario Cancer Institute, University of Toronto, Toronto, Ontario, Canada
Viral hepatitis affects more than 2 billion people worldwide. In particular, no effective treatment exists to abrogate death and liver damage in fulminant hepatitis. Activation of T cells is an initial and critical event in the pathogenesis of liver damage in autoimmune and viral hepatitis. The precise molecular mechanisms that induce T cell-mediated hepatocyte injury remain largely unclear. In mice, T cell-dependent hepatitis and acute liver damage can be modeled using ConA. In this study, we examined the role of the adhesion receptor LFA-1 in ConA-induced acute hepatic damage using LFA-1-/- (CD11a) mice. Massive liver cell apoptosis and metabolic liver damage were observed in LFA-1+/+ mice following ConA injection. By contrast, LFA-1-/- mice were completely resistant to ConA-induced hepatitis and none of the LFA-1-/- mice showed any hepatic damage. Whereas activated hepatic T cells remained in the liver in LFA-1+/+ mice, activated T cells were rapidly cleared from the livers of LFA-1-/- mice. Mechanistically, T cells from LFA-1-/- mice showed markedly reduced cytotoxicity toward liver cells as a result of impaired, activation-dependent adhesion. Importantly, adoptive transfer of hepatic T cells from LFA-1+/+ mice, but not from LFA-1-/- mice, sensitized LFA-1-/- mice to ConA-induced hepatitis. Thus, LFA-1 expression on T cells is necessary and sufficient for T cell-mediated liver damage in vivo. These results provide the first genetic evidence on an adhesion receptor, LFA-1, that has a crucial role in fulminant hepatitis. These genetic data identify LFA-1 as a potential key target for the treatment of T cell-mediated hepatitis and the prevention of liver damage.
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