CD8+ T cell tolerance following antigen recognition on hepatocytes

doi:10.1016/j.jaut.2009.08.005

Journal of Autoimmunity

Volume 34, Issue 1, February 2010, Pages 15-22

https://doi.org/10.1016/j.jaut.2009.08.005 Get rights and content

Abstract

Hepatocytes, the predominant cell type in the liver, are the main cell infected by the hepatitis C virus (HCV) and represent important targets for immune therapy. Although early studies suggested that this parenchymal cell expresses low levels of class I MHC molecules, hepatocytes are emerging as important players in intrahepatic immune responses. Not only do they express high levels of molecules important in antigen presentation, but their expression of these molecules in vivo is also polarized towards the lumen of the sinusoids, thus maximising the efficiency of T cell activation. Electron micrographs indicate that interactions between T cells and hepatocytes occur in vivo via fenestrations in the sinusoidal endothelial layer. In this article, we will review the data showing that hepatocytes function as antigen presenting cells in vivo, and explore the fate of T cells activated by this cell type. We propose that primary activation of naïve CD8+ T cells by hepatocytes is a critical event occurring during the very early stages of a HCV infection, that contributes to progression to viral persistence via the removal of virus-specific T cells from the T cell repertoire.

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-K^b 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-K^b 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-K^b 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-K^b 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 (CFSE^low 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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ReviewCD8+ T cell tolerance following antigen recognition on hepatocytes

Abstract

Introduction

Section snippets

Hepatocytes are effective antigen presenting cells in vitro

Naïve CD8+ T cells activated by hepatocytes in vivo

How do naïve T cells interact with hepatocytes?

Outcome of primary T cell activation by hepatocytes in vivo

Molecular pathways responsible for the death of T cells activated by hepatocytes in vivo

Lymphocyte trafficking influences the kinetic of peripheral deletion in the liver

Fate of LN-activated T cells recirculating to the liver

Implications of these findings for understanding HCV persistence

Why does the liver induce tolerance?

Conclusion

Acknowledgements

Hepatology

Trends Immunol

J Hepatol

Gastroenterology

J Biol Chem

Immunity

Gastroenterology

Cell Immunol

Semin Immunol

Cell Immunol

J Pediatr Surg

The hepatic immune system

Crit Rev Immunol

T lymphocytes interact with hepatocytes through fenestrations in murine liver sinusoidal endothelial cells

Hepatology

Hepatocytes express abundant surface class I MHC and efficiently use transporter associated with antigen processing, tapasin, and low molecular weight polypeptide proteasome subunit components of antigen processing and presentation pathway

J Immunol

Hepatocytes induce functional activation of naive CD8+ T lymphocytes but fail to promote survival

Eur J Immunol

Death by neglect as a deletional mechanism of peripheral tolerance

Int Immunol

Distinct mechanisms of extrathymic T cell tolerance due to differential expression of self antigen

Int Immunol

Expression in transgenic mice of class I histocompatibility antigens controlled by the metallothionein promoter

Proc Natl Acad Sci U S A

Peripheral deletion of autoreactive CD8+ T cells in transgenic mice expressing H-2Kb in the liver

Eur J Immunol

Antigen-specific primary activation of CD8+ T cells within the liver

J Immunol

The site of primary T cell activation is a determinant of the balance between intrahepatic tolerance immunity

J Clin Investig

Differential priming of CD8 CD4 T-cells in animal models of autoimmune hepatitis cholangitis

Hepatology

Complete differentiation of CD8+ T cells activated locally within the transplanted liver

J Exp Med

Local intrahepatic CD8+ T cell activation by a non-self-antigen results in full functional differentiation

J Immunol

Expression of class I and class II major histocompatibility complex antigens on human hepatocytes

Hepatology

CTL access to tissue antigen is restricted in vivo

J Immunol

Intermittence of blood flow in liver sinusoids, studied by high-resolution in vivo microscopy

Am J Physiol

Role of primary intrahepatic T-cell activation in the ‘liver tolerance effect’

Immunol Cell Biol

The liver sieve: considerations concerning the structure and function of endothelial fenestrae, the sinusoidal wall and the space of disse

Hepatology

A two-step model for the induction of organ-specific autoimmunity

Novartis Found Symp

Regulation of activator protein-1 and NF-kappa B in CD8+ T cells exposed to peripheral self-antigens

J Immunol

Review
CD8+ T cell tolerance following antigen recognition on hepatocytes