Necroinflammatory liver disease in BALB/c background, TGF-beta 1-deficient mice requires CD4+ T cells.

Rudner LA, Lin JT, Park IK, Cates JM, Dyer DA, Franz DM, French MA, Duncan EM, White HD, Gorham JD
J Immunol. 2003 170 (9): 4785-92

PMID: 12707360 · DOI:10.4049/jimmunol.170.9.4785

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.

MeSH Terms (18)

Animals Autoimmune Diseases CD4-Positive T-Lymphocytes Crosses, Genetic Cytotoxicity, Immunologic Female Genetic Predisposition to Disease Hepatitis, Animal Immunity, Cellular Lymphocyte Depletion Male Mice Mice, Inbred BALB C Mice, Knockout Necrosis T-Lymphocyte Subsets Transforming Growth Factor beta Transforming Growth Factor beta1

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