Necroinflammatory liver disease in BALB/c background, TGF-β1-deficient mice requires CD4+ T cells

Lynnie A. Rudner, Jack T. Lin, Il Kyoo Park, Justin M.M. Cates, Darci A. Dyer, Douglas M. Franz, Margaret A. French, Elizabeth M. Duncan, Hillary D. White, James D. Gorham

Research output: Contribution to journalArticlepeer-review

36 Scopus citations

Abstract

The etiology of autoimmune liver disease is poorly understood. BALB/c mice deficient in the immunoregulatory cytokine TGF-β1 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-β1-/- 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- β1-/- mice were rendered deficient in B and T cells by crossing them with BALB/c-recombinase-activating gene 1-/- mice. BALB/c-TGF-β1-/-/recombinase-activating gene 1-/- double-knockout mice showed extended survival and did not develop necroinflammatory liver disease. The cytolytic activity of BALB/c-TGF-β1-/- hepatic lymphocytes was assessed using an in vitro CTL assay. CTL activity was much higher in BALB/c-TGF-β1-/- 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-β1-/- 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-β1-/- mice and demonstrate the importance of CD4+ T cells in disease pathogenesis in vivo. Furthermore, TGF-β1 has a critical role in homeostatic regulation of the hepatic immune system, inhibiting the development or expansion of hepatic cytolytic CD4+ T cells.

Original languageEnglish
Pages (from-to)4785-4792
Number of pages8
JournalJournal of Immunology
Volume170
Issue number9
DOIs
StatePublished - May 1 2003

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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