Necroinflammatory Liver Disease in BALB/c Background, TGF-β1-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-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.

TGF-β1 Regulates Antigen-Specific CD4+ T Cell Responses in the Periphery

“…At 10 and 11 days of age, ALT levels were elevated in TGF-␤1 Ϫ/Ϫ mice compared to TGF-␤1 ϩ/Ϫ mice ( p Ͻ 0.0001; Fig. 6C), a kinetic pattern consistent with our previously published studies (5). Thus, in TGF-␤1 Ϫ/Ϫ mice, the development of perturbations in the CD4 ϩ T cell repertoire is detectable in the liver at 3-4 days of age, in the spleen at 7 days of age, and precedes both CD4 ϩ T cell accumulation in the liver and lungs and the onset of detectable liver damage.…”

“…On the BALB/c background, TGF-␤1 Ϫ/Ϫ mice develop a marked necroinflammatory liver disease, with a striking hepatic T cell lymphocytosis, accompanied by lymphocyte-mediated organ destruction within 2 wk of birth (4). The pathogenic role of CD4 ϩ cells in the phenotype of TGF-␤1 Ϫ/Ϫ mice is well established, because depletion of the CD4 ϩ T cell subset prevents the development of necroinflammatory liver disease (5). Moreover, MHC class II Ϫ/Ϫ TGF-␤1 Ϫ/Ϫ double-deficient mice, in which mature CD4 ϩ T cells fail to develop, do not develop inflammatory disease (6).…”

Histone 3 Lysine 9 (H3K9) Methyltransferase Recruitment to the Interleukin-2 (IL-2) Promoter Is a Mechanism of Suppression of IL-2 Transcription by the Transforming Growth Factor-β-Smad Pathway

“…Although multiple types of immune cells can be regulated by TGF-␤, helper T cells actually play a central role in the immunosuppressive effect of TGF-␤; this is deduced from the observation that the neonatal lethality of TGF-␤1-deficient mice is eliminated by depletion of CD4 ϩ T cells (6) and that the crossing of TGF-␤1-deficient mice onto a MHC class II null background prevents the inflammation that they would otherwise develop (7). One of the most important effects of TGF-␤ on T cells is the suppression of IL-2 production (8), which leads to the anti-proliferative effect of TGF-␤ on activated T cells.…”

TGF-β1 inhibition of IFN-γ-induced signaling and Th1 gene expression in CD4+ T cells is Smad3 independent but MAP kinase dependent

“…Target organs in TGF-β1 −/− mice accumulate activated Th1 cells (Gorham et al, 2001), and end organ damage is dependent both upon the CD4 + T cell subset (Letterio et al, 1996;Rudner et al, 2003), and the Th1 cytokine IFN-γ (Gorham et al, 2001). Tissues from TGF-β1 −/− mice show evidence of constitutive IFN-γ signaling (McCartney-Francis and Wahl, 2002), indicating that TGF-β1 normally acts to inhibit IFN-γ signaling.…”