Immune outcomes in the liver: Is CD8 T cell fate determined by the environment?

The liver is known for its tolerogenic properties. This unique characteristic is associated with persistent infection of the liver by the hepatitis B and C viruses. Improper activation of cellular adaptive immune responses within the liver and immune exhaustion over time both contribute to ineffective cytotoxic T cell responses to liver-expressed antigens in animal models, and likely play a role in incomplete clearance of chronic hepatitis virus infections in humans. However, under some conditions, functional immune responses can be elicited against hepatic antigens, resulting in control of hepatotropic infections. In order to develop improved therapeutics in immune-mediated chronic liver diseases, including viral hepatitis, it is essential to understand how intrahepatic immunity is regulated. This review focuses on CD8 T cell immunity directed towards foreign antigens expressed in the liver, and explores how the liver environment dictates the outcome of intrahepatic CD8 T cell responses. Potential strategies to rescue unresponsive CD8 T cells in the liver are also discussed.