title: Necroinflammatory liver disease in BALB/c background, TGF-beta 1-deficient mice requires CD4+ T cells.
abstract: The etiology of autoimmune liver disease is poorly understood. BALB/c mice deficient in the immunoregulatory cytokine TGF-beta1 spontaneously develop necroinflammatory liver disease, but the immune basis for the development of this pathology has not been demonstrated. Here, we show that BALB/c-TGF-beta1(-/-) mice exhibit abnormal expansion in hepatic mononuclear cells (MNCs) compared with wild-type littermate control mice, particularly in the T cell and macrophage lineages. To test whether lymphocytes of the adaptive immune system are required for the spontaneous development of necroinflammatory liver disease, BALB/c-TGF-beta1(-/-) mice were rendered deficient in B and T cells by crossing them with BALB/c-recombinase-activating gene 1(-/-) mice. BALB/c-TGF-beta1(-/-)/recombinase-activating gene 1(-/-) double-knockout mice showed extended survival and did not develop necroinflammatory liver disease. The cytolytic activity of BALB/c-TGF-beta1(-/-) hepatic lymphocytes was assessed using an in vitro CTL assay. CTL activity was much higher in BALB/c-TGF-beta1(-/-) hepatic MNCs compared with littermate control hepatic MNCs and was particularly pronounced in the CD4(+) T cell subset. Experimental depletion of CD4(+) T cells in young BALB/c-TGF-beta1(-/-) mice prevented the subsequent development of necroinflammatory liver disease, indicating that CD4(+) T cells are essential for disease pathogenesis in vivo. These data definitively establish an immune-mediated etiology for necroinflammatory liver disease in BALB/c-TGF-beta1(-/-) mice and demonstrate the importance of CD4(+) T cells in disease pathogenesis in vivo. Furthermore, TGF-beta1 has a critical role in homeostatic regulation of the hepatic immune system, inhibiting the development or expansion of hepatic cytolytic CD4(+) T cells.
authors.affiliation: Department of Pathology, Dartmouth Medical School, Lebanon, NH 03756, USA.
authors.forename: Lynnie A
authors.initials: LA
authors.lastname: Rudner
authors.forename: Jack T
authors.initials: JT
authors.lastname: Lin
authors.forename: Il-Kyoo
authors.initials: IK
authors.lastname: Park
authors.forename: Justin M M
authors.initials: JM
authors.lastname: Cates
authors.forename: Darci A
authors.initials: DA
authors.lastname: Dyer
authors.forename: Douglas M
authors.initials: DM
authors.lastname: Franz
authors.forename: Margaret A
authors.initials: MA
authors.lastname: French
authors.forename: Elizabeth M
authors.initials: EM
authors.lastname: Duncan
authors.forename: Hillary D
authors.initials: HD
authors.lastname: White
authors.forename: James D
authors.initials: JD
authors.lastname: Gorham
mesh_terms: D000818:Animals; D001327:Autoimmune Diseases / Q000235:genetics / Q000276:immunology / Q000473:pathology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000473:pathology; D003433:Crosses, Genetic; D003602:Cytotoxicity, Immunologic / Q000235:genetics; D005260:Female; D020022:Genetic Predisposition to Disease; D006520:Hepatitis, Animal / Q000235:genetics* / Q000276:immunology* / Q000473:pathology; D007111:Immunity, Cellular / Q000235:genetics; D008212:Lymphocyte Depletion; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D009336:Necrosis; D016176:T-Lymphocyte Subsets / Q000276:immunology / Q000473:pathology; D016212:Transforming Growth Factor beta / Q000172:deficiency* / Q000235:genetics* / Q000502:physiology; D053773:Transforming Growth Factor beta1
chemical_list: C508961:Tgfb1 protein, mouse; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1