Spontaneous Chronic Liver Inflammation in a Transgenic Mouse Model of Autoimmune Hepatitis: Impact and Regulation of Autoreactive CD8+ T Cells

Autoimmune hepatitis (AIH) is a chronic inflammatory liver disease of unknown cause. Autoreactive T cells are believed to trigger the destruction of hepatocytes but the pathogenesis of AIH remains poorly understood. To investigate liver-specific CD8⁺ T-cell responses as well as the impact and regulation of autoreactive CD8⁺ T cells in the pathogenesis of AIH, we have generated transgenic mice that express the influenza virus hemagglutinin (HA) model antigen under the control of albumin regulatory elements exclusively in the liver (Alb-HA mice), affording presentation of the antigen by hepatocytes and by professional APCs. Adoptive transfer of HA-specific naive CD8⁺ T cells into Alb-HA mice leads to an activation of autoreactive CD8⁺ T cells and elicits transient hepatitis. Alb-HA/CL4-TCR transgenic mice, in which the majority of CD8⁺ T cells express a HA-specific TCR, spontaneously develop persistent hepatitis characterized by moderate liver inflammation and mildly elevated serum alanine aminotransferase level. Liver infiltrates are dominated by HA-specific CD8⁺ T cells that display diminished TCR expression, no particular signs of apoptosis induction, reduced proliferative capabilities and only little effector function upon restimulation with HA peptide, compatible with the state of T-cell anergy. Moreover, liver infiltrates are enriched for CD4⁺/CD25⁺/FoxP3⁺ regulatory T cells that are potent suppressors of CD8⁺ T-cell activation in vitro, suggesting that regulatory CD4⁺ T cells contribute to the suppression of a broad HA-specific autoimmune response. Our results show that even if many liver-specific CD8⁺ T cells are constantly generated that mediate chronic hepatitis, peripheral tolerance mechanisms such as the induction of T-cell anergy and the induction/expansion of regulatory CD4⁺ T cells protect the liver normally from severe autoimmunity towards hepatocytes.