Common lymphatic endothelial and vascular endothelial receptor-1 mediates the transmigration of regulatory T cells and B cells across hepatic sinusoidal endothelium

Abstract

BackgroundAdult inflammatory liver diseases are driven by lymphocyte infiltration of liver tissue. Lymphocyte recruitment occurs within the unique low shear environment of the hepatic sinusoids. These channels are lined by hepatic sinusoidal endothelial cells (HSEC) which lack conventional adhesion receptors such as selectins, leading us to investigate the role of unconventional adhesion molecules. The common lymphatic endothelial and vascular endothelial receptor-1 (CLEVER-1) is a C-type lectin that has been shown to mediate lymphocyte recruitment to lymphatic endothelium. MethodsWe studied the expression of CLEVER-1 in human liver tissue by immunohistochemistry and immunofluorescence. We proceeded to confirm the expression of CLEVER-1 in isolated HSEC in vitro. Flow based adhesion assays were performed with adhesion blocking antibodies to elucidate the functional role of CLEVER-1. These studies were extended to visualise lymphocyte recruitment and transendothelial migration with immunofluorescence staining and confocal microscopy. Migration of lymphocyte subsets was also studied with tracking software. FindingsCLEVER-1 was expressed at sites of lymphocyte trafficking within the inflamed human liver, particularly the hepatic sinusoids, neovessels of the fibrous septum, and tertiary lymphoid follicles. Furthermore, CLEVER-1 was also detected in the sinusoids and supplying vessels of hepatocellular carcinomas. Functional assays with HSEC showed that CLEVER-1 mediated the transendothelial migration of peripheral blood lymphocytes with preferential activity for regulatory T cells and B cell subsets. Detailed confocal analysis visualised a novel transcellular route of migration by regulatory T cells. B cells also demonstrated altered migratory capacity compared with T cells. InterpretationThese results suggest that CLEVER-1 has a role in modulating the recruitment of regulatory T cells and B cells to the human liver. This C-type lectin could be a potential therapeutic target for chronic inflammatory liver disease and hepatocellular cancer. FundingWellcome Trust.