PD-L1 is induced in hepatocytes by viral infection and by interferon- and - and mediates T cell apoptosis

Marcus Mhlbauer, Martin Fleck, Christian Schtz, Thomas Weiss, Matthias Froh, Christian Blank, Jrgen Schölmerich, Claus Hellerbrand'Correspondence information about the author Claus HellerbrandEmail the author Claus Hellerbrand

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DOI: https://doi.org/10.1016/j.jhep.2006.05.007

 

B7-H1 (PD-L1) is a B7-family member that binds to programmed death-1 (PD-1). Recently, deficiency of PD-L1 has been demonstrated to result in accelerated hepatocyte damage in experimental autoimmune hepatitis, and PD-L1 was suggested to play a critical role in regulating T cell homeostasis. Absence of PD-1 enhanced proliferation of T cells in adenovirus-infected livers and resulted in a rapid clearance of the virus. Here, we aimed to get more insight into hepatic PD-L1 expression, regulation and function.

 

Methods

PD-L1 expression was analyzed by quantitative PCR and FACS-analysis in primary human liver cells and hepatoma cells. Furthermore, coculture experiments with primary human T cells or Jurkat T cells were established.

 

Results

In addition to nonparenchymal liver cells, also hepatocytes constitutively expressed low levels of PD-L1. PD-L1 expression in hepatocytes was strongly enhanced by activated T cells and viral infection, and markedly augmented by further stimulation with type I or type II interferons. Moreover, PD-L1 expression on hepatocytes induced apoptosis in T cells.

 

Conclusions

Our results suggest a novel bidirectional interaction between hepatocytes and lymphocytes modulated by PD-L1 expression in hepatocytes, which may contribute to the unique immunological properties of the liver.

Impairment of T-cell responses in chronic hepatitis B. T cells circulate in the liver through the sinusoidal network, in which they come into contact with hepatocytes and antigen-presenting cells (Kupffer cells and liver sinusoidal endothelial cells). During chronic hepatitis B virus infection, CD8 T cells in the liver encounter virus particles, viral antigens, and infected hepatocytes. They interact with infected hepatocytes and Kupffer cells through the T-cell receptor (TCR)-MHC class I-peptide complex. Hepatocytes over-expressing PD-L1 during chronic infection provide CD8 T cells with an inhibitory signal via the PD-1 pathway. This negative signal results in the impairment of T-cell functions: decreases in proliferation, cytotoxic function and in the production of anti-viral cytokines (IFN- and TNF-). The presence of a large number of regulatory T cells (Tregs) and high levels of IL-10 secretion also contribute to T-cell exhaustion.

 

Keywords:

PD-L1, B7-H1, PD-1, Apoptosis, Liver, Hepatocytes, Tolerance

Abbreviations:

PD-1 (Programmed death-1), PD-L1 (Programmed death-ligand-1), HSC (Hepatic stellate cells), PHH (Primary human hepatocytes)

 

1.. https://www.journal-of-hepatology.eu/article/S0168-8278(06)00291-1/abstract

2. https://www.researchgate.net/figure/49758888_fig3_Impairment-of-T-cell-responses-in-chronic-hepatitis-B-T-cells-circulate-in-the-liver