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Review
Immune outcomes in the liver: Is CD8 T cell fate determined by the environment?
Yik Chun Wong1, , , Szun Szun Tay1, ‡, Geoffrey W. McCaughan2, David G. Bowen1, †, Patrick Bertolino1, †, ,
1 Liver Immunology Group, Centenary Institute and AW Morrow Gastroenterology and Liver Centre, University of Sydney and Royal Prince Alfred Hospital, Sydney, NSW, Australia
2 Liver Cancer and Injury Group, Centenary Institute and AW Morrow Gastroenterology and Liver Centre, University of Sydney and Royal Prince Alfred Hospital, Sydney, NSW, Australia
Received 30 March 2015, Revised 22 May 2015, Accepted 26 May 2015, Available online 20 June 2015
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doi:10.1016/j.jhep.2015.05.033
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Summary
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.
Abbreviations
APCs, antigen-presenting cells; CTLs, cytotoxic CD8 T cells; DCs, dendritic cells; HBV, hepatitis B virus; HCV, hepatitis C virus; ICAM-1, intercellular adhesion molecule-1; IL, interleukin; LCMV, lymphocytic choriomeningitis virus; LNs, lymph nodes; LSECs, liver sinusoidal endothelial cells; MHC-I, major histocompatibility complex class I; PD-1, programmed death 1; PD-L1, programmed death ligand-1; PD-L2, programmed death ligand-2; rAAV, recombinant adeno-associated virus; TCR, T cell receptor; TLR, toll-like receptor
Keywords
Cytotoxic T cells; Tolerance; Immunity; Viral hepatitis; Antigen load; CD8 T cell exhaustion; CD4 T cell help
Introduction
The liver is the target organ of the hepatitis B and C viruses (HBV, HCV), which are associated with the development of chronic liver disease. It is estimated that over 500 million people worldwide are persistently infected with HBV or HCV, representing a major global health problem of considerable human and financial costs. However, HBV and HCV infections are not always persistent: more than 90% of HBV infection in adults and 20% of HCV infections result in viral control or clearance. The reasons why the same viruses persist in some individuals but are cleared in others, and why other hepatotropic viruses, such as hepatitis A, are more effectively eliminated remain unclear. It is likely that these two divergent outcomes are related to the paradoxical immunological properties of the liver itself.
Although effective immune response can be elicited within the liver, under some circumstances the liver induces a state of immune unresponsiveness known as tolerance. This phenomenon underpins the spontaneous acceptance of allogeneic liver transplants observed in several animal models (reviewed in [1]). Injection of antigens via the portal route resulting in direct delivery to the liver [2], and targeting gene expression to the liver [3], both often lead to tolerance. While this intriguing tolerogenic property of the liver has long been known, the mechanisms underlying this phenomenon are not yet completely understood. It is tempting to speculate that some pathogens exploit this tolerogenic property to persist within the liver.
The hallmark of an efficient immune response is the generation of effector cells that eliminate infected cells and/or secrete cytokines that suppress pathogen replication or recruit other arms of the immune response to promote pathogen clearance. CD8 T cells are critical for pathogen clearance, as after activation, they acquire the ability to kill infected cells and secrete cytokines which have direct anti-microbial properties (reviewed in [4]). In the liver, functional cytotoxic CD8 T cells (CTLs) are essential for the resolution of acute HBV [5] and HCV [6] infections. Consistent with this, virus-specific CD8 T cells isolated from patients chronically infected with HBV or HCV have impaired function. This failure to generate a productive anti-viral response results in persistent viral replication that promotes chronic liver disease [7], [8], [9] and [10]. Therefore, the induction of a functional CD8 T cell response against hepatic antigens is associated with better clinical outcomes. In this review, we first discuss the mechanism of T cell activation and the signals required for generating an optimal CD8 T cell response, then the factors that might lead to loss of CD8 T cell responses to liver-expressed antigen and thus promote chronic hepatotropic infections.
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