Hepatic stellate cells veto CD8 T cell activation by a CD54-dependent mechanism

The role of the liver in T cell tolerance is mainly achieved via the functions of tolerogenic hepatic antigen-presenting cells (APCs) and regulatory T cells. Of particular interest in these experiments, hepatic stellate cells (HSCs) have been documented to possess multiple immune functions, ranging from immunogenic antigen presentation to induction of T cell apoptosis. Here, we demonstrate a novel characteristic of stellate cells: the vetoing of naive CD8 T cell priming. The activation of naive T cells by dendritic cells, artificial APCs or PMA/Ionomycin was prevented via a cell contact-dependent mechanism. This was the case when using murine and human HSCs, but not hepatocytes. The activation state of HSCs was vital to the extent of T cell activation inhibition. Specifically, HSCs from fibrotic livers demonstrate the most pronounced veto function. From a mechanistic viewpoint, we could show that it was the high expression level of CD54 that not only restricted IL–2 receptor but also IL–2 expression in T cells. This was proven to be the key to the inhibitory effect, as exogenous IL–2 could overcome the HSC veto function. With these results, we demonstrate a novel attribute of HSCs: the local skewing of the hepatic immune response, resulting in the inhibition of local stimulation of naive T cells. In conclusion, these results strongly indicate a beneficial role in hepatic fibrosis, as CD54 expression on HSCs might attenuate further T cell activation. Additionally, we were able to identify IL–2 as the key cytokine in the mediation of local T cell immunity in order to overcome hepatic tolerance.