Abstract
The liver is an immune-privileged organ that can deactivate autoreactive T cells. Yet in autoimmune hepatitis (AIH), autoreactive T cells can defy hepatic control and attack the liver. To elucidate how tolerance to self-antigens is lost during AIH pathogenesis, we generated a spontaneous mouse model of AIH, based on recognition of an MHC class II–restricted model peptide in hepatocytes by autoreactive CD4+ T cells. We found that the hepatic peptide was not expressed in the thymus, leading to deficient thymic deletion and resulting in peripheral abundance of autoreactive CD4+ T cells. In the liver, autoreactive CD4+ effector T cells accumulated within portal ectopic lymphoid structures and maturated toward pathogenic IFN-γ and TNF coproducing cells. Expansion and pathogenic maturation of autoreactive effector T cells was enabled by a selective increase of plasticity and instability of autoantigen-specific Tregs but not of nonspecific Tregs. Indeed, antigen-specific Tregs were reduced in frequency and manifested increased IL-17 production, reduced epigenetic demethylation, and reduced expression of Foxp3. As a consequence, autoantigen-specific Tregs had a reduced suppressive capacity, as compared with that of nonspecific Tregs. In conclusion, loss of tolerance and the pathogenesis of AIH were enabled by combined failure of thymic deletion and peripheral regulation.
Highlights
Autoimmune diseases are caused by a tissue-damaging immune response of lymphocytes recognizing self-antigens [1]
We constructed a mutated invariant chain molecule (CD74) in which the CLIP peptide sequence was replaced by the LCMV GP61–80 peptide sequence and inserted the mutated gene flanked by loxP sites into the Rosa26 gene, as has been done before with a similar construct [34] (Figure 1A). These mice with inducible glycoprotein (GP) peptide expression were bred with Smarta mice that are transgenic for the Smarta1 T cell receptor recognizing the GP61–80 peptide [35]
We found that virtually all GP-reactive T cells were subjected to thymic deletion in Itgax-iGP_Smarta mice (Figure 1E; 0.68%; P < 0.0001)
Summary
Autoimmune diseases are caused by a tissue-damaging immune response of lymphocytes recognizing self-antigens [1]. Many autoreactive T cells are efficiently deleted at an immature state in the thymus, it has been demonstrated that self-reactive T cells are a constitutive part of the mature lymphocyte repertoire in healthy individuals [2,3,4]. The activation of these mature autoreactive T cells seems to be tightly controlled by various mechanisms, first and foremost by Tregs [4,5,6]. Autoreactive T cell activation rarely produces more than subclinical, self-limited autoimmune episodes in most subjects. The reasons why some individuals develop self-sustained autoimmune diseases, despite these regulatory mechanisms, are not clear
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