Fig. 1. (A) Receptor–ligand pairs directing cells to the liver. Vascular Adhesion Protein-1 (VAP-1) is an adhesion molecule, prominent on hepatic endothelium, that promotes the liver localization of NK cells, CD8+ T cells and CD4+ T cells of the Th2 subset [1,2]. VAP-1 binds to Sialic Acid-binding Immunoglobulin-like Lectin (Siglec) molecules; T cell and NK cell adhesion acts via Siglec-10, while granulocyte adhesion to VAP-1 is mediated by Siglec-9 [3,4], as well as the interaction of CD44 with hyaluronan [5]. Integrin-mediated adhesion receptors also play an important role in the localization of lymphocytes to the liver. Vascular Cell Adhesion Molecule-1 (VCAM-1) binds to Very Late Antigen-4 (VLA-4; also known as a4b1-integrin) and this interaction is important in the hepatic localization of activated CD8+ T cells, and Th1-type CD4+ T cells [2,6]. These adhesion molecules are involved in antigen-independent homing to the liver, but when T cells recognize an antigen, Intercellular Adhesion Molecule-1 (ICAM-1) assumes greater significance. This is the case both for naive, and for already-activated CD8+ T cells [6,7]. When the hepatic vasculature is inflamed, additional adhesion molecules are expressed. Of particular interest is Mucosal Addressin Cell Adhesion Molecule-1 (MAdCAM-1), which is upregulated by both IL-1b and TNF-a [8], and engages the a4b7 integrin that is prominently expressed on intestinal lymphocytes. This interaction might account for the hepatic trapping of activated gut-derived T cells in inflammatory bowel diseases [9]. (B) Endothelial interactions and transmigration. VAP-1 is a signaling molecule. Ligation by antibodies results in endothelial activation, with signaling via PI-3 kinase, MAP kinases and NF-kappaB, resulting in the increased expression of a battery of adhesion molecules including ICAM-1, VCAM-1 and L-selectin, and also in the secretion of the chemokine CXCL8, a powerful neutrophil attractant [10]. The fenestrae that penetrate the Liver Sinusoidal Endothelial Cells are sites where ICAM-1 and VAP-1 molecules form clusters together with Stabilin-1 (also known as Common Lymphocytic Endothelial and Vascular Endothelial Receptor-1, CLEVER-1). During the migration of human T-regulatory (CD4+, FoxP3+) T cells across cultures of human liver endothelial cells, VAP-1 and ICAM-1 contribute to the adhesion of the cells while Stabilin-1 is critical for transmigration [11]. The