Tissue Determinants of Antiviral Immunity in the Liver

Abstract

The liver is an organ bearing important metabolic and immune functions. Hepatocytes are the main metabolically active cells of the liver and are the target of infection by hepatotropic viruses. Virus-specific CD8 T cells are essential for the control of hepatocyte infection with hepatotropic viruses but may be subject to local regulation of their effector function. Here, we review our current knowledge of the tissue determinants of antiviral immunity in the liver. Liver Sinusoidal Endothelial Cells (LSECs) not only allow through their fenestrations the access of circulating virus-specific CD8 T cells to engage in direct contact with infected hepatocytes without the need for extravasation but also cross-present viral antigens released from infected hepatocytes to these CD8 T cells. Two important features of LSECs and hepatocytes contribute to antiviral immune surveillance and liver failure. First, CD8 T cell immunity targeting LSECs leads to widespread endothelial cell death and results in sinusoidal microcirculation failure, causing fulminant viral hepatitis, whereas immune-mediated loss of hepatocytes is rapidly compensated by the regenerative capacity of the liver. Second, virus-infected hepatocytes support clearance of infection by responding to TNF, which is released from virus-specific CD8 T cells, with the selective induction of apoptosis. This increased sensitivity for TNF-induced death is caused by reduced mitochondrial resilience in virus-infected hepatocytes and may assist antiviral immunity in preferential targeting of virus-infected hepatocytes. Thus, hepatocytes and LSECs actively contribute to the outcome of antiviral CD8 T cell immunity in the liver. The knowledge of the mechanisms determining CD8 T cell control of hepatotropic viral infection will help to improve strategies to increase antiviral immune surveillance.

Fig. 1

Schematic drawing of priming of CD8 T cells. ( A ) Priming of CD8 T cells by somatic cells, like hepatocytes, leads to activation and differentiation into functionally impaired CD8 T cells. ( B ) Cross-priming of CD8 T cells by professional antigen-presenting cells (APC) with exogenous antigen leads and co-stimulatory signals leads to functional maturation into effector CD8 T cells.

Fig. 2

Mechanism of TNF induced cell death in virus-infected hepatocytes. ( A ) Stimulation of virus-infected hepatocytes by TNF leads to triggering of TNF receptor 1 (TNFR1) leading to activation of NF-kB that will lead to transcription of pro-survival genes, blocking e.g. caspase 8 activation. In parallel, TNFR1 stimulation leads to NADPH-dependent reactive oxygen species (ROS) formation that activates Phospholipase C gamma thereby producing IP3. IP3 triggers the IP3 receptor in the endoplasmic reticulum (ER) leading to release of calcium ions that are taken up and stored by mitochondria. ( B ) Virus infection of hepatocytes leads to reduced mitochondrial stress resilience with regards to calcium signaling. Calcium released from the ER triggers mitochondrial permeability transition leading to the release of mitochondrial cytochrome C that activates caspase 3. Caspase 8 might be activated by cleavage in a feedback loop by caspase 3 leading to enhanced apoptosis signaling.