Essential Role of the Adhesion Receptor LFA-1 for T Cell-Dependent Fulminant Hepatitis

• Published in: The Journal of immunology (1950) Vol. 169; no. 12; pp. 7087 - 7096
• Main Authors: Matsumoto, Goichi, Tsunematsu, Satoshi, Tsukinoki, Kei-ichi, Ohmi, Yasushi, Iwamiya, Mariko, Oliveira-dos-Santos, Antonio, Tone, Daisuke, Shindo, Junichi, Penninger, Josef M
• Format: Journal Article
• Language: English
• Published: United States Am Assoc Immnol 15-12-2002
• Subjects: Adoptive Transfer; Animals; Antibodies, Monoclonal - administration & dosage; Antigens - biosynthesis; Antigens, Surface; Cell Adhesion - genetics; Cell Adhesion - immunology; Cell Line; Chemical and Drug Induced Liver Injury - etiology; Chemical and Drug Induced Liver Injury - genetics; Chemical and Drug Induced Liver Injury - immunology; Chemical and Drug Induced Liver Injury - prevention & control; Concanavalin A - toxicity; Cytotoxicity, Immunologic - genetics; Injections, Intravenous; Intercellular Adhesion Molecule-1 - immunology; Killer Cells, Natural - immunology; Killer Cells, Natural - metabolism; Killer Cells, Natural - transplantation; Lectins, C-Type; Liver - immunology; Liver - pathology; Lymphocyte Activation - genetics; Lymphocyte Activation - immunology; Lymphocyte Function-Associated Antigen-1 - biosynthesis; Lymphocyte Function-Associated Antigen-1 - genetics; Lymphocyte Function-Associated Antigen-1 - physiology; Mice; Mice, Inbred C57BL; Mice, Knockout; NK Cell Lectin-Like Receptor Subfamily B; Protein Biosynthesis; Proteins; Receptors, Antigen, T-Cell, alpha-beta - biosynthesis; T-Lymphocyte Subsets - immunology; T-Lymphocyte Subsets - metabolism; T-Lymphocyte Subsets - transplantation
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.169.12.7087

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.