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

J Immunol. 2011 Apr 1;186(7):4147-55. doi: 10.4049/jimmunol.1002961. Epub 2011 Mar 2.


The common lymphatic endothelial and vascular endothelial receptor (CLEVER-1; also known as FEEL-1 and stabilin-1) is a recycling and intracellular trafficking receptor with multifunctional properties. In this study, we demonstrate increased endothelial expression of CLEVER-1/stabilin-1 at sites of leukocyte recruitment to the inflamed human liver including sinusoids, septal vessels, and lymphoid follicles in inflammatory liver disease and tumor-associated vessels in hepatocellular carcinoma. We used primary cultures of human hepatic sinusoidal endothelial cells (HSEC) to demonstrate that CLEVER-1/stabilin-1 expression is enhanced by hepatocyte growth factor but not by classical proinflammatory cytokines. We then showed that CLEVER-1/stabilin-1 supports T cell transendothelial migration across HSEC under conditions of flow with strong preferential activity for CD4 FoxP3(+) regulatory T cells (Tregs). CLEVER-1/stabilin-1 inhibition reduced Treg transendothelial migration by 40% and when combined with blockade of ICAM-1 and vascular adhesion protein-1 (VAP-1) reduced it by >80%. Confocal microscopy demonstrated that 60% of transmigrating Tregs underwent transcellular migration through HSEC via ICAM-1- and VAP-1-rich transcellular pores in close association with CLEVER-1/stabilin-1. Thus, CLEVER-1/stabilin-1 and VAP-1 may provide an organ-specific signal for Treg recruitment to the inflamed liver and to hepatocellular carcinoma.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Carcinoma, Hepatocellular / blood supply
  • Carcinoma, Hepatocellular / immunology*
  • Carcinoma, Hepatocellular / pathology
  • Cell Adhesion Molecules, Neuronal / physiology*
  • Cells, Cultured
  • Chemotaxis, Leukocyte / immunology*
  • Endothelium, Vascular / immunology*
  • Endothelium, Vascular / metabolism
  • Endothelium, Vascular / pathology
  • Forkhead Transcription Factors / biosynthesis
  • Humans
  • Inflammation Mediators / physiology
  • Liver / immunology*
  • Liver / metabolism
  • Liver / pathology
  • Liver Diseases / immunology
  • Liver Diseases / metabolism
  • Liver Diseases / pathology
  • Liver Neoplasms / blood supply
  • Liver Neoplasms / immunology*
  • Liver Neoplasms / pathology
  • Receptors, Lymphocyte Homing / physiology*
  • T-Lymphocytes, Regulatory / immunology*
  • T-Lymphocytes, Regulatory / metabolism
  • T-Lymphocytes, Regulatory / pathology*
  • Tumor Cells, Cultured


  • Cell Adhesion Molecules, Neuronal
  • FOXP3 protein, human
  • Forkhead Transcription Factors
  • Inflammation Mediators
  • Receptors, Lymphocyte Homing
  • STAB1 protein, human