title: End-organ damage in a mouse model of fulminant liver inflammation requires CD4+ T cell production of IFN-gamma but is independent of Fas.
abstract: Fulminant inflammation in the liver is often accompanied by the accumulation of IFN-gamma-producing T cells. The BALB/c-Tgfb1(-/-) mouse exhibits extensive, spontaneously developing necroinflammation in the liver, accompanied by the accumulation of IFN-gamma-producing CD4(+) and CD8(+) T cells. Liver damage depends on the presence of an intact Ifng gene. We determined the relevant cellular source(s) of IFN-gamma. In Tgfb1(-/-) liver, CD4(+) T cells were more numerous than CD8(+) T cells and NK cells, and produced more IFN-gamma. Depletion of CD4(+) T cells eliminated both the elevation in plasma IFN-gamma and aspartate aminotransferase, whereas depletion of CD8(+) T cells did not. Rag1(-/-)Tgfb1(-/-) mice exhibited neither IFN-gamma elevation nor tissue damage, indicating that NK cells are not sufficient. IFN-gamma was required for strong overexpression of class II genes but not for CD4(+) T cell activation, oligoclonal expansion, or accumulation in the liver. The T cell inhibitory molecule PD-L1 was strongly expressed in Tgfb1(-/-) livers, ruling out a lack of PD-L1 expression as an explanation for aberrant liver T cell activation. Finally, whereas Tgfb1(-/-) CD4(+) T cells overexpressed Fas ligand, hepatocellular damage was observed in Fas(lpr/lpr)Tgfb1(-/-) mice, indicating that liver pathology is Fas independent. We conclude that liver damage in this model of fulminant autoimmune hepatitis is driven by CD4(+) T cell production of IFN-gamma, is independent of both CD8(+) T cells and the Fas ligand/Fas pathway, and is not explained by a lack of PD-L1 expression.
authors.affiliation: Department of Microbiology and Immunology, Dartmouth Medical School, Lebanon, NH 03756, USA.
authors.forename: Richard T
authors.initials: RT
authors.lastname: Robinson
authors.forename: Jing
authors.initials: J
authors.lastname: Wang
authors.forename: James G
authors.initials: JG
authors.lastname: Cripps
authors.forename: Michael W
authors.initials: MW
authors.lastname: Milks
authors.forename: Kathryn A
authors.initials: KA
authors.lastname: English
authors.forename: Todd A
authors.initials: TA
authors.lastname: Pearson
authors.forename: James D
authors.initials: JD
authors.lastname: Gorham
mesh_terms: D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D004195:Disease Models, Animal; D053222:Fas Ligand Protein / Q000235:genetics / Q000502:physiology; D019693:Hepatitis, Autoimmune / Q000276:immunology* / Q000378:metabolism / Q000473:pathology*; D007249:Inflammation / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D007371:Interferon-gamma / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D008099:Liver / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D017114:Liver Failure, Acute / Q000276:immunology* / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D008822:Mice, Transgenic; D053773:Transforming Growth Factor beta1 / Q000235:genetics; D019014:fas Receptor / Q000235:genetics / Q000502:physiology
chemical_list: D053222:Fas Ligand Protein; C508961:Tgfb1 protein, mouse; D053773:Transforming Growth Factor beta1; D019014:fas Receptor; D007371:Interferon-gamma