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End-Organ Damage in a Mouse Model of Fulminant Liver Inflammation Requires CD4⁺ T Cell Production of IFN- but Is Independent of Fas¹

Richard T. Robinson^*, Jing Wang, James G. Cripps^*, Michael W. Milks, Kathryn A. English, Todd A. Pearson and James D. Gorham^2,*,

^* Department of Microbiology and Immunology, and Department of Pathology, Dartmouth Medical School, Lebanon, NH 03756

Fulminant inflammation in the liver is often accompanied by the accumulation of IFN--producing T cells. The BALB/c-Tgfb1^–/– mouse exhibits extensive, spontaneously developing necroinflammation in the liver, accompanied by the accumulation of IFN--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-. In Tgfb1^–/– liver, CD4⁺ T cells were more numerous than CD8⁺ T cells and NK cells, and produced more IFN-. Depletion of CD4⁺ T cells eliminated both the elevation in plasma IFN- and aspartate aminotransferase, whereas depletion of CD8⁺ T cells did not. Rag1^–/–Tgfb1^–/– mice exhibited neither IFN- elevation nor tissue damage, indicating that NK cells are not sufficient. IFN- 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/lprTgfb1^–/– 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-, is independent of both CD8⁺ T cells and the Fas ligand/Fas pathway, and is not explained by a lack of PD-L1 expression.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by National Institutes of Health Grants AI053056 (J.D.G.), DK073904 (J.D.G.) and P20RR16437 from the Centers of Biomedical Research Excellence Program of the National Center for Research Resources, as well as by a grant from the Hitchcock Foundation (J.D.G.). J.W. was supported by a Samuel A. Hamacher Autoimmune Hepatitis Postdoctoral Research Fellowship from the American Liver Foundation. R.T.R. was supported by National Institutes of Health Training Grants T32AI07363 and T32AR07576.

² Address correspondence and reprint request to Dr. James D. Gorham, Department of Pathology, Dartmouth Medical School, One Medical Center Drive, Lebanon, NH 03756. E-mail address: James.D.Gorham{at}Dartmouth.edu

³ Abbreviations used in this paper: AIH, autoimmune hepatitis; ALT, alanine aminotransferase; AST, aspartate aminotransferase; CD4SP, CD4⁺ single positive; FasL, Fas ligand; NPC, nonparenchymal cell.