Break of T cell ignorance to a viral antigen in the liver induces hepatitis.
To study peripheral tolerance of CD8 T cells to a classically MHC-restricted peptide Ag expressed in hepatocytes, ALB1 transgenic (tg) mice expressing the CTL epitope GP33 of the lymphocytic choriomeningitis virus glycoprotein under control of the mouse albumin promoter were generated. ALB1 mice exclusively expressed the GP33 transgene in the liver and, at a 100- to 1000-fold lower level, in the thymus. TCR-tg mice specific for the GP33 epitope were used to directly follow GP33-specific T cells in vivo. These experiments revealed that 1) thymic expression of the GP33 transgene led to incomplete central deletion of TCR-tg cells; and 2) peripheral TCR-tg cells in ALB1 mice ignored the GP33 transgene expressed in hepatocytes. Ignorance of adoptively transferred TCR-tg cells in ALB1 mice was broken by infection with lymphocytic choriomeningitis virus, leading to induction of hepatitis in ALB1, but not in control, mice. Taken together, we have established a novel model of virus-induced CD8 T cell-mediated autoimmune hepatitis in mice and demonstrate that naive CD8 T cells may ignore Ags expressed in the liver.
Voehringer
D
D
Institute for Medical Microbiology and Hygiene, Department of Immunology, University of Freiburg, Freiburg, Germany.
Blaser
C
C
Grawitz
A B
AB
Chisari
F V
FV
Buerki
K
K
Pircher
H
H
D019264:Adoptive Transfer; D000818:Animals; D000956:Antigens, Viral / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology*; D018984:Epitopes, T-Lymphocyte / Q000235:genetics / Q000276:immunology; D006023:Glycoproteins / Q000096:biosynthesis / Q000235:genetics; D006524:Hepatitis, Viral, Animal / Q000209:etiology* / Q000235:genetics / Q000276:immunology*; D007108:Immune Tolerance / Q000235:genetics; D008099:Liver / Q000276:immunology* / Q000378:metabolism / Q000821:virology*; D008212:Lymphocyte Depletion; D008216:Lymphocytic Choriomeningitis / Q000235:genetics / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D008822:Mice, Transgenic; D010446:Peptide Fragments / Q000096:biosynthesis / Q000235:genetics; D011948:Receptors, Antigen, T-Cell / Q000235:genetics; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D013950:Thymus Gland / Q000276:immunology / Q000378:metabolism; D019076:Transgenes / Q000276:immunology; D014764:Viral Proteins
D000956:Antigens, Viral; D018984:Epitopes, T-Lymphocyte; D006023:Glycoproteins; D010446:Peptide Fragments; D011948:Receptors, Antigen, T-Cell; D014764:Viral Proteins; C094244:glycoprotein peptide 33-41, Lymphocytic choriomeningitis virus