Human liver sinusoidal endothelial cells induce apoptosis in activated T cells: a role in tolerance induction

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Abstract
The liver may have 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. It was hypothesised 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. By using immunoassays and western blot analysis, the fate of activated T cells when incubated with human LSEC isolated from normal healthy livers was investigated. Evidence that activated (approximately 30%) but not non-activated T cells undergo apoptosis on incubation with human LSEC in mixed cell cultures is provided. 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 proapoptotic molecule Bak. Transforming growth factor beta (TGFbeta) produced constitutively by LSEC is partly responsible for the caspase-induced apoptosis, as neutralising antibodies to TGFbeta markedly attenuated apoptosis, up regulated the antiapoptotic molecule Bcl-2 and partially blocked caspase-3 activity. These findings broaden the potential role of LSEC in immune tolerance and homeostasis of the immune system. This 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.