Genetic Regulation of Autoimmune Disease: BALB/c Background TGF-β1-Deficient Mice Develop Necroinflammatory IFN-γ-Dependent Hepatitis

Abstract

Autoimmune hepatitis (AIH) in humans arises spontaneously in genetically susceptible individuals and is associated with the presence of Th1 cells in the liver. The understanding of AIH has advanced more slowly than that of other organ-specific autoimmune diseases, however, largely because of the lack of an appropriate animal model. We now describe a new mouse model characterized by spontaneous development of necroinflammatory hepatitis that is restricted by genetic background. Mice deficient in the immunomodulatory cytokine TGF-β1 were extensively back-bred to the BALB/c background. The BALB/c background dramatically modified the phenotype of TGF-β1−/− mice: specifically, BALB/c-TGF-β1−/− mice developed a lethal necroinflammatory hepatitis that was not observed in TGF-β1−/− mice on a different genetic background. BALB/c background TGF-β1−/− livers contained large numbers of activated CD4+ T cells that produced large quantities of IFN-γ, but little IL-4, identifying them as Th1 cells. BALB/c background TGF-β1−/−/IFN-γ−/− double knockout mice, generated by cross-breeding, did not develop necroinflammatory hepatitis, demonstrating that IFN-γ is mechanistically required for its pathogenesis. This represents the first murine model of hepatitis that develops spontaneously, is restricted by genetic background, and is dependent upon the Th1 cytokine IFN-γ, and that thus recapitulates these important aspects of AIH.

TGFβ1 and Treg cells: alliance for tolerance

“…Tgfb1 −/− T cells do differentiate into T h 17 cells in vitro in the presence of added TGFβ1 and anti-CD3, suggesting that the lack of T h 17-cell development in Tgfb1 −/− mice is owing to the presence of abundant IFN-γ, the absence of TGFβ1 or both. In Tgfb1 −/− Ifng −/− mice, inflammation is eliminated only in the liver but not in the heart and lungs [35]. This suggests that pathogenic T h 17 cells might be induced by IL-6 in the absence of IFN-γ and TGFβ1, hence causing disease and early lethality in Tgfb1 −/− Ifng −/− mice.…”

“…Consistent with recent observations that TGFβ1 and IL-6 are essential for T h 17-cell differentiation, T h 17 cells are absent in Tgfb1 −/− mice, suggesting that Tgfb1 −/− T cells cause autoimmune disease without differentiating into T h 17 cells [19,34]. Because Tgfb1 −/− T cells produce interferon (IFN)-γ but not IL-17, it is possible that IFN-γ produced by T h 1 cells inhibits T h 17-cell development [22,34,35]. Tgfb1 −/− T cells do differentiate into T h 17 cells in vitro in the presence of added TGFβ1 and anti-CD3, suggesting that the lack of T h 17-cell development in Tgfb1 −/− mice is owing to the presence of abundant IFN-γ, the absence of TGFβ1 or both.…”

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

“…BALB/c background TGF-␤1 Ϫ/Ϫ mice develop a dramatic hepatic CD4 ϩ T cell lymphocytosis with accompanying severe liver damage by 10 -11 days of age (4). The accumulation of CD4 ϩ T cells in liver may be due either to an expansion of a population of CD4 ϩ T cells expressing a full repertoire of TCR V␤-chains, or to an expansion of a CD4 ϩ T cell population expressing only one or a few TCR V␤ chains.…”

“…Mice homozygous for a targeted deletion in the gene encoding TGF-␤1 (TGF-␤1 Ϫ/Ϫ mice) develop a striking peripheral organ T cell lymphocytosis within a few weeks of birth, as well as inflammatory pathologic changes in several organs, primarily the liver, lungs, and heart (2, 3). 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).…”

“…Both IFN-␥ and TNF-␣ are toxic to hepatocytes (19 -21); Fas is constitutively expressed on hepatocytes and its engagement rapidly causes hepatocyte apoptosis (22,23). Livers from TGF-␤1 Ϫ/Ϫ mice exhibit high levels of expression of mRNAs encoding IFN-␥, TNF-␣, and Fas ligand, suggesting that the elaboration of these molecules may participate in the disease process, and indeed TGF-␤1 Ϫ/Ϫ /IFN-␥ Ϫ/Ϫ double knockout mice are protected from the development of necroinflammatory liver disease (4).…”