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Mice with a targeted deletion in TGF-beta1 spontaneously develop CD4+ T-cell-dependent multifocal inflammatory disease and autoimmune pathology. T cells from TGF-beta1-/- mice are strongly activated, but the mechanisms that lead to T-cell activation and organ pathology are not well understood. Recent work shows that TGF-beta1 raises the threshold for signaling through the TCR, suppressing the response of T cells to mitogenic stimuli. This suggests the possibility that CD4+ T cells in TGF-beta1-/- mice become aberrantly activated and cause damage in response to physiologic inputs that ordinarily are not sufficient for cell activation, such as homeostatic MHC-TCR interactions, cytokines, or adhesion molecules. This model predicts that pathology is largely antigen-independent, and that CD4+ T cells, regardless of antigen specificity, will become activated in TGF-beta1-/- mice, with subsequent organ pathology. To test this model, we crossed BALB/c-TGF-beta1-/- mice with the DO11.10 TCR transgenic mouse. To obviate the possible development of nonclonotypic TCRs, we also bred in a deficiency in RAG-1. Cohorts of highly inbred BALB/c background TGF-beta1-/- mice with an increasingly restricted CD4+ T-cell repertoire (TGF-beta1-/- mice; DO11.10-TGF-beta1-/- mice; DO11.10-RAG-1-/-TGF-beta1-/- mice) were then analyzed for inflammatory organ pathology and T-cell activation. The data show that progressively restricting the CD4+ T-cell repertoire improved survival, ameliorated target organ pathology, and reduced T-cell activation to control levels. Therefore, these results find no support for the involvement of atypical T-cell activation pathways in disease in TGF-beta1-/- mice. Rather, T-cell activation and pathology in TGF-beta1-/- mice appear to be functions of typical TCR activation pathways. This supports the hypothesis that immune pathology in TGF-beta1-/- mice is self-antigen triggered.

Autoimmune hepatitis (AIH) is mediated by a T-cell attack upon liver parenchyma. Susceptibility to the development of AIH is genetically determined. While particular MHC haplotypes are known risk factors, it has been widely speculated that autoimmune liver damage can be regulated by additional genetic loci unlinked to MHC. However, evidence for the existence of such loci in humans is scant. We examined the contribution of the MHC in a murine model of autoimmune hepatocellular injury. BALB/c mice lacking the immunoregulatory cytokine transforming growth factor-beta1 (TGF-beta1) rapidly develop autoimmune T-helper 1-mediated necroinflammatory liver disease. Susceptibility to liver damage is strictly regulated by genetic background. Whereas TGF-beta1-deficient mice on the BALB/c background develop necroinflammatory liver disease, TGF-beta1-deficient mice on the 129/CF-1 genetic background do not. We asked whether MHC locus haplotype is the principal determinant of genetic susceptibility to liver disease in this model system. BALB/c mice harbor the H-2d haplotype. We used a 'haplotype swapping' approach to generate H-2b or H-2k congenic BALB-background TGF-beta1-deficient mice. In addition, F1 (BALB/c x 129/CF-1)-TGF-beta1-deficient mice were generated. As determined by plasma transaminase levels and histopathology, severe necroinflammatory liver disease developed in all BALB-background TGF-beta1-deficient mice, regardless of H-2 haplotype, but developed neither in 129/CF-1-TGF-beta1-deficient mice nor in F1 (BALB/c x 129/CF-1)-TGF-beta1-deficient mice. Thus, H-2d is neither necessary nor sufficient for the development of necroinflammatory liver disease in BALB-background TGF-beta1-deficient mice. This constitutes the first direct evidence that susceptibility to autoimmune hepatocellular damage, at least in mice, can be determined by genetic loci distinct from the MHC.