Liver sinusoidal endothelial cells: Their unique role in immune tolerance

Abstract

Background The liver may play a role in peripheral tolerance, by serving as a site for trapping, apoptosis and phagocytosis of activated T cells. It is not known which hepatic cells are involved in these processes. We hypothesized that liver sinusoidal endothelial cells (LSEC) which are strategically placed for participation in the regulation of sinusoidal blood flow, and express markers involved in recognition, sequestration, and apoptosis, may contribute to peripheral tolerance by inducing apoptosis of activated T cells. Methods Using immunoassays and western blot analysis we investigated the fate of activated T cells when incubated with human LSEC isolated from normal healthy livers. Results We provide evidence that activated (app. 30%) but not non-activated T cells undergo apoptosis upon incubation with human LSEC in mixed cell cultures. No difference in the results was observed when unstimulated and cytokine stimulated LSEC were used. T cell-LSEC contact is required for induction of apoptosis. Apoptosis induced by LSEC was associated with caspase 8 and 3 activity and strong expression of the pro-apoptotic molecule Bak. TGF-beta produced constitutively by LSEC is partly responsible for the caspase-induced apoptosis, since neutralizing antibodies to TGF-beta markedly attenuated apoptosis, upregulated the anti-apoptotic molecule Bcl-2 and partially blocked caspase-3 activity. Conclusion These findings broaden the potential role of LSEC in immune tolerance and homeostasis of the immune system. The present study may provide insight for exploring the mechanisms of immune tolerance by liver allografts, immune escape by some liver pathogens including hepatitis C and pathogenesis of liver diseases.