{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,13]],"date-time":"2026-05-13T18:13:48Z","timestamp":1778696028470,"version":"3.51.4"},"reference-count":48,"publisher":"Oxford University Press (OUP)","issue":"5","license":[{"start":{"date-parts":[[2009,3,1]],"date-time":"2009-03-01T00:00:00Z","timestamp":1235865600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2009,3,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Fulminant inflammation in the liver is often accompanied by the accumulation of IFN-\u03b3-producing T cells. The BALB\/c-Tgfb1\u2212\/\u2212 mouse exhibits extensive, spontaneously developing necroinflammation in the liver, accompanied by the accumulation of IFN-\u03b3-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-\u03b3. In Tgfb1\u2212\/\u2212 liver, CD4+ T cells were more numerous than CD8+ T cells and NK cells, and produced more IFN-\u03b3. Depletion of CD4+ T cells eliminated both the elevation in plasma IFN-\u03b3 and aspartate aminotransferase, whereas depletion of CD8+ T cells did not. Rag1\u2212\/\u2212Tgfb1\u2212\/\u2212 mice exhibited neither IFN-\u03b3 elevation nor tissue damage, indicating that NK cells are not sufficient. IFN-\u03b3 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\u2212\/\u2212 livers, ruling out a lack of PD-L1 expression as an explanation for aberrant liver T cell activation. Finally, whereas Tgfb1\u2212\/\u2212 CD4+ T cells overexpressed Fas ligand, hepatocellular damage was observed in Faslpr\/lprTgfb1\u2212\/\u2212 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-\u03b3, is independent of both CD8+ T cells and the Fas ligand\/Fas pathway, and is not explained by a lack of PD-L1 expression.<\/jats:p>","DOI":"10.4049\/jimmunol.0803417","type":"journal-article","created":{"date-parts":[[2009,2,20]],"date-time":"2009-02-20T22:41:32Z","timestamp":1235169692000},"page":"3278-3284","source":"Crossref","is-referenced-by-count":30,"title":["End-Organ Damage in a Mouse Model of Fulminant Liver Inflammation Requires CD4+ T Cell Production of IFN-\u03b3 but Is Independent of Fas"],"prefix":"10.1093","volume":"182","author":[{"given":"Richard T","family":"Robinson","sequence":"first","affiliation":[{"name":"Department of Microbiology and Immunology"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jing","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Pathology, Dartmouth Medical School , Lebanon, NH 03756"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"James G","family":"Cripps","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Michael W","family":"Milks","sequence":"additional","affiliation":[{"name":"Department of Pathology, Dartmouth Medical School , Lebanon, NH 03756"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kathryn A","family":"English","sequence":"additional","affiliation":[{"name":"Department of Pathology, Dartmouth Medical School , Lebanon, NH 03756"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Todd A","family":"Pearson","sequence":"additional","affiliation":[{"name":"Department of Pathology, Dartmouth Medical School , Lebanon, NH 03756"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"James D","family":"Gorham","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology"},{"name":"Department of Pathology, Dartmouth Medical School , Lebanon, NH 03756"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2009,3,1]]},"reference":[{"key":"2025032622242001800_R1","first-page":"161","article-title":"Phenotypical analysis and cytokine release of liver-infiltrating and peripheral blood T lymphocytes from patients with chronic hepatitis of different etiology.","volume-title":"Liver","year":"1994"},{"key":"2025032622242001800_R2","first-page":"1416","article-title":"Autoreactive CD4+ LKM-specific and anticlonotypic T-cell responses in LKM-1 antibody-positive autoimmune hepatitis.","volume-title":"Hepatology","year":"1996"},{"key":"2025032622242001800_R3","first-page":"S35","article-title":"Hepatitis C pathogenesis: mechanisms of viral clearance and liver injury.","volume-title":"Liver Transpl.","year":"2003"},{"key":"2025032622242001800_R4","first-page":"89","article-title":"Immunopathogenesis of hepatitis C virus infection.","volume-title":"Clin. Liver Dis.","year":"2003"},{"key":"2025032622242001800_R5","first-page":"279","article-title":"CD4+ T-lymphocytes mediate ischemia\/reperfusion-induced inflammatory responses in mouse liver.","volume-title":"J. Clin. Invest.","year":"1997"},{"key":"2025032622242001800_R6","first-page":"472","article-title":"Cytochrome P450IID6-specific CD8 T cell immune responses mirror disease activity in autoimmune hepatitis type 2.","volume-title":"Hepatology","year":"2007"},{"key":"2025032622242001800_R7","first-page":"462","article-title":"IFN-\u03b3 plays a critical role in T cell-dependent liver injury in mice initiated by concanavalin A.","volume-title":"Gastroenterology","year":"1996"},{"key":"2025032622242001800_R8","first-page":"1227","article-title":"A pivotal involvement of IFN-\u03b3 in the pathogenesis of acetaminophen-induced acute liver injury.","volume-title":"FASEB J.","year":"2002"},{"key":"2025032622242001800_R9","first-page":"356","article-title":"Effects of immunomodulation with IFN-\u03b3 on hepatic ischemia-reperfusion injury.","volume-title":"Shock","year":"1999"},{"key":"2025032622242001800_R10","first-page":"2","article-title":"Autoantibodies and autoantigens in autoimmune hepatitis: important tools in clinical practice and to study pathogenesis of the disease.","volume-title":"J. Autoimmune Dis.","year":"2004"},{"key":"2025032622242001800_R11","first-page":"589","article-title":"Mechanisms of autoimmune hepatitis.","volume-title":"Pediatr. Transplant.","year":"2004"},{"key":"2025032622242001800_R12","first-page":"643","article-title":"Formiminotransferase cyclodeaminase is an organ-specific autoantigen recognized by sera of patients with autoimmune hepatitis.","volume-title":"Gastroenterology","year":"1999"},{"key":"2025032622242001800_R13","first-page":"70","article-title":"Limited T cell receptor V\u03b2-chain repertoire of liver-infiltrating T cells in autoimmune hepatitis.","volume-title":"J. Hepatol.","year":"1998"},{"key":"2025032622242001800_R14","first-page":"806","article-title":"T cell repertoire in the liver of patients with autoimmune hepatitis.","volume-title":"Hum. Immunol.","year":"1999"},{"key":"2025032622242001800_R15","first-page":"353","article-title":"Genetics in autoimmune hepatitis.","volume-title":"Semin. Liver Dis.","year":"2002"},{"key":"2025032622242001800_R16","first-page":"250","article-title":"Genetic susceptibilities for immune expression and liver cell injury in autoimmune hepatitis.","volume-title":"Immunol. Rev.","year":"2000"},{"key":"2025032622242001800_R17","first-page":"1447","article-title":"Immunohistochemical features of the portal tract mononuclear cell infiltrate in chronic aggressive hepatitis.","volume-title":"Arch. Dis. Child.","year":"1992"},{"key":"2025032622242001800_R18","first-page":"816","article-title":"Cellular expression of TNF-\u03b1 and IFN-\u03b3 in the liver biopsies of children with chronic liver disease.","volume-title":"J. Hepatol.","year":"1994"},{"key":"2025032622242001800_R19","first-page":"303","article-title":"Cytokines and the pathogenesis of non-alcoholic steatohepatitis.","volume-title":"Gut","year":"2005"},{"key":"2025032622242001800_R20","first-page":"614","article-title":"Chronic active hepatitis in transgenic mice expressing IFN-\u03b3 in the liver.","volume-title":"Proc. Natl. Acad. Sci. USA","year":"1994"},{"key":"2025032622242001800_R21","first-page":"51S","article-title":"TGF-\u03b21, Th1 responses, and autoimmune liver disease.","volume-title":"Transfusion","year":"2005"},{"key":"2025032622242001800_R22","first-page":"550","article-title":"MHC-independent genetic regulation of liver damage in a mouse model of autoimmune hepatocellular injury.","volume-title":"Lab. Invest.","year":"2005"},{"key":"2025032622242001800_R23","first-page":"4785","article-title":"Necroinflammatory liver disease in BALB\/c background, TGF-\u03b21-deficient mice requires CD4+ T cells.","volume-title":"J. Immunol.","year":"2003"},{"key":"2025032622242001800_R24","first-page":"71","article-title":"TGF-\u03b21 regulates antigen-specific CD4+ T cell responses in the periphery.","volume-title":"J. Immunol.","year":"2007"},{"key":"2025032622242001800_R25","first-page":"815","article-title":"Restriction of the CD4+ T-cell receptor repertoire prevents immune pathology in TGF-\u03b21 knockout mice.","volume-title":"Lab. Invest.","year":"2006"},{"key":"2025032622242001800_R26","first-page":"6413","article-title":"Genetic regulation of autoimmune disease: BALB\/c background TGF-\u03b21-deficient mice develop necroinflammatory IFN-\u03b3-dependent hepatitis.","volume-title":"J. Immunol.","year":"2001"},{"key":"2025032622242001800_R27","first-page":"2370","article-title":"Fas\/Fas ligand deficiency results in altered localization of anti-double-stranded DNA B cells and dendritic cells.","volume-title":"J. Immunol.","year":"2001"},{"key":"2025032622242001800_R28","first-page":"5950","article-title":"TGF-\u03b21 uses distinct mechanisms to inhibit IFN-\u03b3 expression in CD4+ T cells at priming and at recall: differential involvement of Stat4 and T-bet.","volume-title":"J. Immunol.","year":"2005"},{"key":"2025032622242001800_R29","first-page":"4082","article-title":"Disparate roles for TNF-\u03b1 and Fas ligand in concanavalin A-induced hepatitis.","volume-title":"J. Immunol.","year":"1998"},{"key":"2025032622242001800_R30","first-page":"9944","article-title":"TGF-\u03b21 controls expression of major histocompatibility genes in the postnatal mouse: aberrant histocompatibility antigen expression in the pathogenesis of the TGF-\u03b21 null mouse phenotype.","volume-title":"Proc. Natl. Acad. Sci. 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Med.","year":"2003"},{"key":"2025032622242001800_R34","first-page":"327","article-title":"B7\u2013H1 determines accumulation and deletion of intrahepatic CD8+ T lymphocytes.","volume-title":"Immunity","year":"2004"},{"key":"2025032622242001800_R35","first-page":"2713","article-title":"Suppressed T-cell activation by IFN-\u03b3-induced expression of PD-L1 on renal tubular epithelial cells.","volume-title":"Nephrol. Dial. Transplant.","year":"2004"},{"key":"2025032622242001800_R36","first-page":"5336","article-title":"PD-L1 and PD-L2 are differentially regulated by Th1 and Th2 cells.","volume-title":"Proc. Natl. Acad. Sci. USA","year":"2003"},{"key":"2025032622242001800_R37","first-page":"520","article-title":"PD-L1 is induced in hepatocytes by viral infection and by IFN-\u03b1 and -\u03b3 and mediates T cell apoptosis.","volume-title":"J. Hepatol.","year":"2006"},{"key":"2025032622242001800_R38","first-page":"806","article-title":"Lethal effect of the anti-Fas antibody in mice.","volume-title":"Nature","year":"1993"},{"key":"2025032622242001800_R39","first-page":"129","article-title":"c-Myc partially mediates IFN-\u03b3-induced apoptosis in the primary hepatocyte.","volume-title":"Int. J. Exp. Pathol.","year":"2007"},{"key":"2025032622242001800_R40","first-page":"54","article-title":"Autoimmune hepatitis.","volume-title":"N. Engl. J. Med.","year":"2006"},{"key":"2025032622242001800_R41","first-page":"659","article-title":"HCV persistence and immune evasion in the absence of memory T cell help.","volume-title":"Science","year":"2003"},{"key":"2025032622242001800_R42","first-page":"1033","article-title":"To be or not to be NKT: natural killer T cells in the liver.","volume-title":"Hepatology","year":"2004"},{"key":"2025032622242001800_R43","first-page":"868","article-title":"Polyclonal T-cell responses to cytochrome P450IID6 are associated with disease activity in autoimmune hepatitis type 2.","volume-title":"Gastroenterology","year":"2006"},{"key":"2025032622242001800_R44","first-page":"1545","article-title":"Differential ability of Th1 and Th2 T cells to express Fas ligand and to undergo activation-induced cell death.","volume-title":"Int. Immunol.","year":"1994"},{"key":"2025032622242001800_R45","first-page":"3806","article-title":"Expression of the Fas ligand in cells of T cell lineage.","volume-title":"J. 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