Immunology and Cell Biology (2002) 80, 52–64 Special Feature Recruitment of lymphocytes to the human liver PATRICIA F LALOR, PHILIP SHIELDS, ALLISTER J GRANT and DAVID H ADAMS Liver Research Laboratories, University of Birmingham MRC Centre for Immune Regulation, Institute of Clinical Research, Queen Elizabeth Hospital, Edgbaston, Birmingham, United Kingdom Summary This review discusses the function and localisation of lymphocytes resident within the human liver, under both physiological and pathological conditions. Through description of the mechanisms that mediate lymphocyte recruitment into tissues, this article explains how hepatic endothelial and epithelial cells regulate the recruitment of specific lymphocyte subpopulations. We illustrate that the expression of adhesion molecules and chemokines is crucial to the control of lymphocyte adhesion. Thus, in the normal liver, adhesion molecules such as vascular adhesion protein-1 (VAP-1), intercellular adhesion molecule-1 (ICAM-1) and intercellular adhesion molecule-2 (ICAM-2), and chemokines such as regulated on activation, normal T cell expressed and secreted (RANTES), monocyte chemoattractant protein-1 (MCP-1), macrophage inflammatory protein-1 α (MIP-1α), interferon γ inducible protein-10 (IP-10), MIG and interferon inducible T-cell alpha chemoattractant (ITAC) are involved in lymphocyte binding to different endothelial compartments. However, in response to inflammation or injury, additional expression of adhesion molecules such as VCAM-1, P-selectin and E-selectin, as well as higher levels of chemokines, permits the attraction and retention of specific effector populations of lymphocytes. We also discuss the expression and function of a newly defined adhesion protein, (VAP-1), and suggest that the unique functions of this protein may provide therapeutic potential for the treatment of liver disease. Key words: adhesion molecules, chemokines, endothelium, liver, lymphocyte homing. Introduction The normal liver contains a large number of lymphocytes that include not only specialized NK and NKT cells, but also CD4 and CD8 T cells. Whereas some of these cells are terminally differentiated effector cells that are destined to die by apop- tosis, many of these cells are not and include immunocompe- tent cells that traffic through the liver to provide continuing immune surveillance as well as epithelial-associated effector T cells. In inflammatory liver disease the number of lym- phocytes in the liver increases and the type and distribution of these infiltrating cells will determine the nature of the inflam- mation, for instance, a predominance of parenchymal inflam- mation is a feature of lobular hepatitis associated with viral hepatitis while a predominantly portal infiltrate centred on bile ducts is a feature of the biliary diseases primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC). In this review we discuss the molecular mechanisms that regu- late the entry of lymphocytes to the normal and inflamed liver and thereby determine the patterns of inflammatory damage in liver disease. The liver vasculature The liver has a unique dual blood supply with arterial blood delivered via the hepatic arteries and venous blood from the gut via the portal veins. This complex supply is necessary to allow nutrients from the gut to be transported to the liver, which is thus constantly exposed to gut-derived antigens in the portal blood. Because portal blood also presents a route through which infectious organisms can enter the liver, spe- cific mechanisms have evolved to allow rapid and selective immune responses within this tissue. Thus, the liver contains a large resident and migratory population of lymphocytes and macrophages that provide immune surveillance against foreign antigens (Fig. 1). This population can be rapidly expanded in response to infection or injury by recruiting leucocytes from the circulation, a process that is dependent on the ability of lymphocytes to recognize, bind to and migrate across the endothelial cells that line the hepatic vasculature. The complex nature of the liver vasculature means that there are several points at which lymphocytes can interact with endothelium and be recruited into different anatomical com- partments. The hepatic microvascular system consists of portal venules, hepatic arterioles, sinusoids, central venules and lymphatics. Most blood entering the sinusoids comes from the portal venules, the terminal branches of which enter into the sinusoids at inlets that are protected by contractile sinusoidal lining cells that act as a sphincter to regulate blood entry and, hence, blood flow within the sinusoids. Arterial blood enters the sinusoids through branches of the hepatic arterioles and via occasional direct arterioportal anastomoses at the level of the terminal portal venules. 1 These structures are also contrac- tile and, therefore, contribute to the control of blood within the sinusoids. The sinusoids take the blood through the lobule from the portal tract to the central (terminal vein). Close to the Correspondence: Dr PF Lalor, Liver Research Laboratories, Uni- versity of Birmingham MRC Centre for Immune Regulation, Institute of Clinical Research, Queen Elizabeth Hospital, Edgbaston, Birming- ham B15 2TH, UK. Email: P.F.LALOR@bham.ac.uk Received 16 October 2001; accepted 31 October 2001.