Autoimmunity associated with TGF-beta1-deficiency in mice is dependent on MHC class II antigen expression.

114

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.

Section: Balb/c-tgf-␤1 ϫ/ϫ Livers Have Large Numbers Of Activated Th1mentioning

confidence: 99%

Section: Duration Of Survival Of Tgf-␤1 ϫ/ϫ Mice Is Modified By Genetmentioning

confidence: 99%

mentioning

confidence: 99%

See 1 more Smart Citation

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

Gorham¹,

Lin²,

Sung³

et al. 2001

114

“…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).…”

mentioning

confidence: 99%

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

Robinson

Gorham

2007

T cell expansion typically is due to cognate interactions with specific Ag, although T cells can be experimentally activated through bystander mechanisms not involving specific Ag. TGF-β1 knockout mice exhibit a striking expansion of CD4+ T cells in the liver by 11 days of age, accompanied by CD4+ T cell-dependent necroinflammatory liver disease. To examine whether hepatic CD4+ T cell expansion in TGF-β1−/− mice is due to cognate TCR-peptide interactions, we used spectratype analysis to examine the diversity in TCR Vβ repertoires in peripheral CD4+ T cells. We reasoned that Ag-nonspecific T cell responses would yield spectratype profiles similar to those derived from control polyclonal T cell populations, whereas Ag-specific T cell responses would yield perturbed spectratype profiles. Spleen and liver CD4+ T cells from 11-day-old TGF-β1−/− mice characteristically exhibited highly perturbed nonpolyclonal distributions of TCR Vβ CDR3 lengths, indicative of Ag-driven T cell responses. We quantitatively assessed spectratype perturbation to derive a spectratype complexity score. Spectratype complexity scores were considerably higher for TGF-β1−/− CD4+ T cells than for TGF-β1+/− CD4+ T cells. TCR repertoire perturbations were apparent as early as postnatal day 3 and preceded both hepatic T cell expansion and liver damage. By contrast, TGF-β1−/− CD4+ single-positive thymocytes from 11-day-old mice exhibited normal unbiased spectratype profiles. These results indicate that CD4+ T cells in TGF-β1−/− mice are activated by and respond to self-Ags present in the periphery, and define a key role for TGF-β1 in the peripheral regulation of Ag-specific CD4+ T cell responses.

“…The type I receptor then activates the Smad family of signal transducers (18 -20), as well as Smad-independent pathways involving TGF␤-associated kinase/Ras, Daxx, and protein phosphatase type 2A (PP2A) (21)(22)(23)(24). Mice rendered genetically deficient in one Smad member, Smad3, exhibit immune dysregulation reminiscent of the phenotype seen with impaired TGF-␤ responses (25)(26)(27)(28)(29), suggesting that the Smad pathway is an important mediator of TGF-␤ signaling in the immune system. Smad3 is activated via serine phosphorylation of a C-terminal SSXS motif by the TGF-␤ type I receptor (30).…”

Section: Uncoupling Of Promitogenic and Antiapoptotic Functions Of Ilmentioning

confidence: 99%

Uncoupling of Promitogenic and Antiapoptotic Functions of IL-2 by Smad-Dependent TGF-β Signaling

Nelson

Martyak²,

Thompson

et al. 2003

TGF-β opposes proliferative signaling by IL-2 through mechanisms that remain incompletely defined. In a well-characterized CD8+ T cell model using wild-type and mutated IL-2 receptors, we examined the effects of TGF-β on distinct IL-2 signaling events in CD8+ T cells. IL-2 induces c-myc, cyclin D2, and cyclin E in a redundant manner through the Shc and STAT5 pathways. TGF-β inhibited the ability of either the Shc or STAT5 pathway to induce these genes, as well as T cell proliferation. The inhibitory effects of TGF-β were reversed by expression of a dominant-negative form of Smad3. TGF-β did not impair proximal signaling by Shc or STAT5, and induction of some downstream genes, including cytokine-inducible Src homology-2-containing protein (CIS), bcl-xL, and bcl-2, was spared. Experiments with c-fos, cyclin D2, and CIS reporter genes revealed that promoter-proximal regulatory elements dictate the sensitivity of IL-2 target genes to inhibition by TGF-β. By leaving the Shc and STAT5 pathways functional while inhibiting their target genes selectively, TGF-β was found to uncouple the proliferative and antiapoptotic functions of IL-2. Thus, TGF-β is not a simple antagonist of IL-2, but rather serves to qualitatively modify the IL-2 signal to create a unique pattern of gene expression that neither cytokine can induce independently.