Effects and regulation of autoreactive CD8+ T cells in a transgenic mouse model of autoimmune hepatitis

Abstract

Background & Aims: Autoimmune hepatitis (AIH) is a chronic inflammatory liver disease of unknown etiology. Autoreactive T cells are thought to mediate liver injury, but the pathogenesis of AIH is poorly understood because of the lack of suitable animal models. We established a mouse model to investigate liver-specific T-cell responses and assess the effects and regulation of autoreactive CD8+ T cells in the pathogenesis of AIH. Methods: We generated transgenic mice expressing the influenza virus hemagglutinin (HA) autoantigen under control of mouse albumin regulatory elements and α-fetoprotein enhancers (Alb) specifically in the liver (Alb-HA mice); they were crossed with mice that express a specific T-cell receptor (TCR) (CL4-TCR). CL4-TCR transgenic CD8+ T cells were also adoptively transferred into Alb-HA mice. We investigated immunologic mechanisms of CD8 + T cell-induced liver damage and of counteracting peripheral tolerance. Results: The double-transgenic mice (Alb-HA/CL4-TCR) spontaneously developed chronic, autoimmune-mediated hepatitis, characterized by necroinflammatory lesions, hepatic fibrosis, and increased levels of aminotransferase; these features resembled those of AIH. Interestingly, most liver-infiltrating, HA-specific CD8+ T cells had an anergic phenotype; regulatory CD4+CD25+Foxp3+ T cells accumulated in the inflamed liver. Conclusions: The continuous development of a few, HA-specific CD8+ effector T cells is sufficient to induce chronic hepatitis. Peripheral tolerance mechanisms such as induction of T-cell anergy and accumulation of regulatory CD4+CD25+Foxp3 + T cells protect the liver from severe damage. Our mouse model that spontaneously develops chronic autoimmune-mediated hepatitis provides a new tool to investigate autoantigen-specific T-cell responses and regulatory mechanisms involved in the prevention and pathogenesis of AIH. © 2010 by the AGA Institute.