ReviewCD8+ T cell tolerance following antigen recognition on hepatocytes
Introduction
Hepatocytes comprise 70–80% of all liver cells and are large cells, approximately 30 μm in diameter [1]. These polygonal cells are arranged in plates and lie underneath the liver sinusoids, a position essential for the synthesis of proteins, cholesterol, bile salts and phospholipids. In addition to their metabolic function, hepatocytes have emerged as antigen presenting cells (APCs) for CD8+ T cells in the liver. This immunological function is facilitated by the polarized expression of major histocompatibility (MHC) class I and intercellular adhesion molecule-1 (ICAM-1) molecules towards the sinusoidal lumen [2]. These molecules are required for T cell activation, as is contact between naïve CD8+ T cells and hepatocytes recently evidenced by electron microscopy [2]. Hepatocytes are not the only potential APCs in the liver. Liver sinusoidal endothelial cells (LSECs), Kupffer cells (KCs), stellate cells and resident hepatic dendritic cells (DCs) have all been shown to be possess capacity as APCs.
Studies using transgenic mouse models suggest that T cells activated by hepatocytes die prematurely leading to tolerance, thus, it is possible that antigens presented by hepatocytes compromise the subsequent immune response. This phenomenon may have important clinical sequelae: for example, hepatocytes are the main cell target of the hepatitis C virus (HCV). Direct antigen presentation by virally infected hepatocytes might play an important role in the earliest stages of HCV infection, when antigen cross-presentation in the lymph nodes (LNs) is not yet occurring. In approximately 80% of patients, HCV infection persists. This review will focus on primary T cell activation by hepatocytes and the consequence of this activation on T cell phenotype and fate, as well as the potential influence of this mechanism of T cell activation in tolerance and hepatotropic infections.
Section snippets
Hepatocytes are effective antigen presenting cells in vitro
Based on immunohistochemistry experiments performed on liver sections, expression of MHC molecules on hepatocytes has been generally regarded as being low or absent. However, this conclusion has been questioned by recent studies indicating that expression of these molecules on hepatocytes is in fact high. Mouse hepatocytes express 7–16 fold more Class 1 molecules on the cell surface compared to splenocytes [3] but due to their large size hepatocytes display a lower density of peptide/MHC
Naïve CD8+ T cells activated by hepatocytes in vivo
The ability of hepatocytes to induce activation of naïve CD8+ T cells in vivo is more complex to demonstrate than in vitro studies for two main reasons. Firstly, antigen expressed by hepatocytes could be cross-presented by professional APCs in the liver or lymphoid tissues. Secondly, T cells recirculate relatively quickly between different organs and it is difficult to determine where T cells were initially primed. The first obstacle was overcome by using transgenic mouse models in which
How do naïve T cells interact with hepatocytes?
As initially suggested by key experiments performed by Chisari and colleagues involving interactions between previously activated T cells and the liver [16], the key to understanding the distinctive property of the liver in inducing primary T cell activation is likely to be its unique architecture and blood flow, which also facilitate interactions between naïve T cells and hepatocytes [17]. Blood flow in the liver is slow and/or intermittent compared to other solid organs. In addition, blood
Outcome of primary T cell activation by hepatocytes in vivo
Studies performed using transgenic models described above have explored the consequences of T cell activation by hepatocytes in vivo. However, the outcome of this activation is a matter of debate. In the Alb-Kb model in which antigen expression is restricted to hepatocytes, in the absence of pre-existing liver injury, the outcome of intrahepatic activation is tolerance [11], [22]. Despite activation and proliferation of Des-TCR cells in this model, recipient Alb-Kb mice never developed signs of
Molecular pathways responsible for the death of T cells activated by hepatocytes in vivo
Phenotypic and functional analysis of hepatocyte-activated CD8+ T cells suggested these cells received a contrasting program of differentiation compared to LN-activated T cells.
Hepatocyte- and LN-activated CD8+ T cells expressed the majority of activation markers at the same level. However, hepatocyte-activated T cells displayed reduced expression of ICAM-1 and CD25, the alpha chain of the high affinity interleukin-2 receptor (IL-2R) [25]. The other chains of the high affinity IL-2R (CD122 and
Lymphocyte trafficking influences the kinetic of peripheral deletion in the liver
Due to restricted expression of the antigen on hepatocytes in the absence of cross-presentation in the periphery, the Alb-Kb model is ideal to study the recirculation of T cells activated by hepatocytes.
Activation of CFSE-labelled Des-RAG CD8+ T cells transferred into Alb-Kb mice is restricted to the liver (Fig. 3).
To determine whether hepatocyte-activated CD8+ T cells recirculated to the LNs after day 2, the presence of dividing Des-RAG T cells (CFSElow cells) was assessed in the blood, LNs
Fate of LN-activated T cells recirculating to the liver
The outcome of interactions between previously activated effector T cells and liver cells is somewhat controversial. Initial studies suggested the liver tolerance effect was due to the unique ability of the liver to retain activated T cells undergoing apoptosis or actively kill effector T cells recognizing their antigen in situ (“graveyard” theory) [36], [37]. This model implied that all immune responses in the liver would be stifled, however the theory could not account for the presence of
Implications of these findings for understanding HCV persistence
As the liver is clearly able to tolerize both naïve and activated CD8+ T cells it is no surprise that immune responses in the liver are stifled, allowing pathogens such as HCV to establish persistent infections. In fact over 170 million people worldwide are infected with HCV, with approximately 20% of patients developing cirrhosis and 2.5% hepatocellular carcinoma (HCC) [42].
One of the most perplexing facets of HCV, regardless of outcome, is the reported 1–3 month delay in the emergence of a
Why does the liver induce tolerance?
Food- and other non-pathogen-derived antigens have the capacity to travel to the liver from the gut via the portal vein. Initiation of immune responses to such antigens is likely to be harmful, thus there is a decrease in responsiveness to antigens delivered by this pathway, a process referred to as oral tolerance. Tolerance to these antigens occurs mainly in the gut itself through the generation of regulatory T cells (Tregs) [57], [58]. However, the liver is also well situated to play a role
Conclusion
The liver is unique among solid organs in its ability to compete with the LNs for the retention and activation of naïve CD8+ T cells. Whilst primary activation of CD8+ T cells in the LNs induces effector CTLs, T cell activation by hepatocytes is associated with poor effector functions and death in a Bim dependent manner. The predominant site of T cell activation could be a determinant of the outcome of hepatotropic viral infections such as HCV, with activation of high affinity virus-specific T
Acknowledgements
The authors wish to thanks Drs. Andreas Strasser and Lorraine O'Reilly for the generous gift of the Bim antibody.
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