CXCR3 activation promotes lymphocyte transendothelial migration across human hepatic endothelium under fluid flow

T cells infiltrating the inflamed liver express high levels of CXCR3 and show enhanced migration to CXCR3 ligands in chemotactic assays. Moreover, CXCR3 ligands are up-regulated on hepatic endothelium at sites of T-cell infiltration in chronic hepatitis, and their presence correlates with outcome of inflammatory liver disease. We used a flow-based adhesion assay with human hepatic endothelium to investigate the function of CXCR3 on lymphocyte adhesion to and transmigration through hepatic endothelium under physiological conditions of blood flow. To more accurately model the function of in vivo activated CXCR3(high) lymphocytes, we isolated T cells from human liver tissue and studied their behavior in flow-based adhesion assays. We demonstrate that CXCR3 not only promoted the adhesion of effector T cells to endothelium from flow but also drove transendothelial migration. Moreover, these responses could be stimulated either by endogenous CXCR3 ligands secreted by the endothelium or by exogenous CXCR3 ligands derived from other cell types and presented by the endothelium. This study thus demonstrates that activation of CXCR3 promotes lymphocyte adhesion and transendothelial migration under flow and that human hepatic endothelium can present functionally active chemokines secreted by other cell types within the liver.