Cell Adhesion and Migration IV. Lymphocyte trafficking in the intestine and liver *

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1 themes Cell Adhesion and Migration IV. Lymphocyte trafficking in the intestine and liver * M. SALMI, 1 D. ADAMS, 2 AND S. JALKANEN 1 1 MediCity Research Laboratories, University of Turku and National Public Health Institute, Turku, Finland; and 2 Liver Research Laboratories, University of Birmingham and Queen Elizabeth Hospital, Edgbaston, Birmingham B15 2TH, United Kingdom Salmi, M., D. Adams, and S. Jalkanen. Cell Adhesion and Migration. IV. Lymphocyte trafficking in the intestine and liver. Am. J. Physiol. 274 (Gastrointest. Liver Physiol. 37): G1 G6, Naive lymphocytes patrol continuously between the blood and different lymphatic tissues to sample the whole body for foreign antigens. During inflammation, leukocyte recruitment into tissue is enhanced to promote the recruitment of a range of effector cells into the affected area. The complex recirculatory pathways that underlie this process are governed by adhesion receptors on blood-borne leukocytes and by their specific ligands expressed on the luminal aspect of endothelial cells lining the vessels. Gutassociated lymphatic tissues are positioned strategically at the major port of entry for foreign antigens. They form a functionally unified entity that utilizes both the afferent and efferent arms of the immune response to respond to the large array of antigens entering via the gut under normal conditions as well as during inflammation. Once antigens have been absorbed from the gut, they may enter the portal vein and the liver where the immune response can be further regulated by the resident immune cells of the liver. Thus the gut and liver form an important barrier to enteral antigens, and leukocyte recruitment to these sites will need to be carefully regulated to ensure effective immune surveillance. In this article, we describe the current concepts of lymphocyte adhesion in these two organs as revealed by animal models. Subsequently, we discuss how well these principles apply to the lymphocyte-endothelial cell interactions in humans and what additional insights can be obtained from human studies. adhesion molecules; endothelium; inflammation THE BLOOD DISPERSES naive lymphocytes released from primary lymphoid organs throughout the body. These circulating lymphocytes enter secondary lymphatic organs via specialized postcapillary venules, called high endothelial venules (HEV). Antigens are concentrated in lymphatic tissue and presented to lymphocytes by dendritic cells, which migrate into the lymph node via the afferent lymphatics. If a naive lymphocyte, with its unique antigen receptor, does not encounter its cognate antigen in the lymph node, it leaves the tissue by entering the efferent lymphatics and is carried back to *Fourth in a series of invited articles on Cell Adhesion and Migration. the systemic circulation. The same cell is then capable of homing to any other lymphatic tissue in the body. However, if the lymphocyte recognizes its specific antigen in the correct microenvironment of the lymph node, it undergoes clonal expansion into an activated immunoblast, which then also returns to the blood in the efferent lymph. However, unlike naive cells, which migrate through all lymphoid tissues, activated immunoblasts show a remarkable selectivity in their homing and return to the lymphatic tissue in which they were activated and to the nonlymphatic tissues draining into that lymph node (9). There is compelling evidence that peripheral lymph nodes and mucosa-associated lymphoid tissues (gut, respiratory tree, and urogenital system) represent two functionally distinct recirculation routes in terms of immunoblast homing. Although the selectivity of homing is diminished under inflammatory settings, lymphocytes entering the inflamed skin and synovial membrane display functional features that imply that these are distinct homing pathways (6, 18, 22). Freely flowing blood cells traverse the postcapillary venule at a velocity of 500 µm/s, resulting in a shear force that must be overcome before a lymphocyte can adhere to the endothelium lining the vessel and extravasate into tissue. A complex cascade of adhesive interactions involving multiple receptor-ligand pairs on both the leukocyte and the endothelium has evolved to regulate the extravasation of flowing leukocytes (6, 18, 22). Under conditions of shear stress, members of the selectin superfamily (P-selectin, E-selectin, and L- selectin) and their mucin-type glycoprotein ligands [P-selectin glycoprotein ligand-1, mucosal addressin cell adhesion molecule-1 (MAdCAM-1), and peripheral lymph node addressins (PNAd)] are the predominant molecules involved in initiating contacts between the lymphocyte and the endothelial cell (Fig. 1). However, it is likely that other molecules, including vascular adhesion protein-1 (VAP-1) on endothelial cells and possibly hyaluronate, also participate at an early stage, probably in rolling, in the multistep cascade. The contribution of inflammation-inducible VAP-1 to initial interaction between lymphocytes and vascular endothelium has been recently confirmed in an in vivo animal model (19a). The initial transient and reversible interactions lead to tethering and rolling of the leukocyte along the /98 $5.00 Copyright 1998 the American Physiological Society G1

2 G2 LYMPHOCYTE HOMING TO GUT AND LIVER Fig. 1. Adhesion molecules involved in lymphocyte-endothelial cell interactions. The expressing cell type, molecular superfamily, and interactions of adhesion molecules discussed in text are shown. It should be noted that only interactions known to occur between lymphocytes (not granulocytes) and endothelial cells are given. (See Refs. 6, 18, and 22 for a thorough review of these and other homing-related molecules). PSGL-1, P-selectin glycoprotein ligand-1; CLA, cutaneous lymphocyte antigen; LFA-1, lymphocyte functionassociated antigen-1; GlyCAM-1, glycosylation-dependent cell adhesion molecule-1; MAdCAM-1, mucosal addressin cell adhesion molecule-1; VCAM-1, vascular cell adhesion molecule-1; VAP-1, vascular adhesion protein-1; ICAM, intercellular adhesion molecule. Peripheral lymph node addressins are a group of at least 6 glycoproteins, which include CD34 and GlyCAM-1. endothelial cell at a greatly reduced velocity, allowing the rolling cell to be activated. The nature of the physiological stimuli that activate rolling leukocytes is still uncertain, but it is likely to involve signals triggered by the ligation of rolling receptors and/or binding of a special class of chemotactic cytokines called chemokines to specific G protein-linked seven-pass transmembrane receptors. The activation step triggers conformational changes in leukocyte integrins that allow them to bind to counter-receptors on the endothelium such as intercellular adhesion molecule-1 (ICAM-1), ICAM-2, vascular cell adhesion molecule-1 (VCAM-1), and MAd- CAM-1, resulting in firm, stationary adhesion. Such stable, adherent cells can also serve as a nucleus for initial interactions with other circulating leukocytes, which start to roll along the endothelium after binding to the already adherent leukocyte. The adherent cell finally spreads on the endothelium and locates at the endothelial cell junctions, through which it migrates using as yet poorly understood mechanisms involving lymphocyte CD31 and lymphocyte function-associated antigen-1 (LFA-1) and their endothelial ligands and secretion of matrix-degrading metalloproteinases. Many adhesion molecules are constitutively expressed on certain cell types, whereas others can be induced and/or upregulated on inflammation. The selectivity of the adhesion process is controlled not only by cell type-selective expression of functionally active forms of the adhesion molecules but also by the creation of combinatorial selectivity, resulting from the fact that successful migration into a given anatomic location requires at least four successive receptor-ligand interactions. Thus, if successful receptor-ligand interactions fail at any of the stages, extravasation of the leukocyte into tissue will fail. LYMPHOCYTE HOMING TO MUCOSA AND LIVER IN ANIMALS In the gut, a naive lymphocyte that is activated in the Peyer s patches undergoes further differentiation in the local collecting lymph nodes (e.g., mesenteric lymph nodes) before returning to the blood as an immunoblast. The mucosa-derived immunoblast will then selectively reenter the lamina propria of the gut rather than the peripheral lymph nodes to exert its effector functions. Lymphocyte homing to gut is critically dependent on interactions between a lymphocyte 4 7 -integrin and its receptor MAdCAM-1 expressed on mucosal vessels (4). MAdCAM-1 is almost completely confined to mucosal and related vessels and is thus one of the few examples of an endothelial adhesion molecule that is restricted to a particular tissue. Lymphocyte interactions with MAdCAM-1 are particularly complex, because depending on its state of glycosylation MAd- CAM-1 can bind to two distinct lymphocyte receptors, the 4 7 -integrin and L-selectin, and can mediate both rolling and stable adhesion. Thus in Peyer s patch HEV MAdCAM-1 is decorated with unique oligosaccharide determinants that allow it to serve as a ligand for L-selectin and thereby to mediate rolling of naive lymphocytes. In contrast, in the lamina propria, initial rolling interactions between activated lymphocytes and endothelial cells are apparently mediated by binding of the 4 7 -integrin to immunoglobulin-like domains of MAdCAM-1. At both locations, 4 7 -integrin-mad- CAM-1 interaction and possibly LFA-1 secure firm lymphocyte adhesion. The predominant role proposed for 4 7 -integrin in mucosal homing has gained further support from the observation that cell trafficking to mucosal lymphatic tissues is dramatically reduced in 7 -knockout animals (27). Similar to the skin and the mucosal surfaces, the liver is a major site of antigen exposure, with its own lymphatic supply and resident lymphocyte population. The complex vascular anatomy of the liver means that it receives a dual blood supply, from the portal vein and hepatic artery. These vessels enter the portal tracts where their terminal branches empty into the hepatic sinusoids that run between the liver cell plates, before emptying into the hepatic veins and returning to the inferior vena cava. The nature of an inflammatory response in the liver will be determined, at least in part, by where in this system lymphocytes bind to the endothelium and leave the blood to enter the liver tissue. If this occurs in the sinusoids, lymphocytes will

3 LYMPHOCYTE HOMING TO GUT AND LIVER G3 enter the parenchyma, whereas extravasation across portal vessels will result in infiltration of the portal tracts (1). Antigen is presented to naive T cells by dendritic cells in the hepatic lymph nodes. After exposure to antigen, dendritic cells migrate via the hepatic sinusoids to the lymphatics and accumulate selectively in the hepatic lymph nodes in the porta hepatis. Here, they activate naive T cells to differentiate into memory cells that subsequently migrate back to the liver (10). Lymphocytes not retained in the liver return via the lymphatics to the draining hepatic lymph nodes. Intriguingly, hepatic lymphocyte-endothelial interactions take place in sinusoidal vessels under conditions of low-velocity blood flow. Leukocyte interactions with sinusoidal endothelium differ from those involved with postcapillary venules in several important aspects. The characteristic rolling phase of primary adhesion that is seen in interactions with postcapillary venules is not observed, and adhesion to sinusoidal endothelium is unaffected in animals lacking endothelial selectins (29). However, retention of leukocytes in the hepatic sinusoids is adhesion dependent, because it is greatly reduced, although not abolished, in animals that lack ICAM-1 or in those treated with antibodies against ICAM-1 (9a, 29). The paradigm of lymphocyte homing has emerged mainly from studies using continuous endothelium and postcapillary venules in high-velocity vascular beds in lymphoid and inflamed nonlymphoid tissues as models. The unique observations made during studies of the sinusoidal bed in the liver suggest that further studies of specialized vascular beds are required and argue against generalization of the results obtained in more easily accessible model systems. The nature of putative tissue-specific activation signal(s) in gut and liver is unknown at present, since none of the 50 chemokines identified appears to be truly tissue specific. Stable adhesion and diapedesis have not been thoroughly studied either in gut or liver. Activated lymphocytes may use LFA-1-ICAM-1 interactions and other nontissue-specific adhesion molecules to halt and possibly, in the gut, CD31 and ICAM-1 to transmigrate. In the liver sinusoids, the relative lack of CD31 expression suggests that other pathways will be involved. DOES COMPARTMENTALIZATION TO MUCOSAL AND PERIPHERAL LYMPH NODE RECIRCULATORY SYSTEMS EXIST IN HUMANS? Due to the ethical difficulties of studying lymphocyte migration in vivo in humans, most of our knowledge of the migratory behavior of human mucosal lymphocytes has been gathered from in vitro studies. The existence in humans of functionally distinct recirculatory routes via peripheral lymph nodes and mucosa-associated lymphatic tissues (as have been described in the mouse) is strongly supported by the preferential expression of PNAd on peripheral lymph node endothelium and MAdCAM-1 on mucosal vessels (5). Moreover, human mucosal lymphocytes are able to discriminate between vascular endothelium in peripheral lymph nodes and mucosal endothelium, because mucosal lymphocytes display selective binding to mucosal endothelium in frozen section adhesion assays. As with the mouse, human mucosal lymphocytes use mainly 4 7 -integrin to bind to vascular endothelium at mucosal sites, although LFA-1 and CD44 also contribute (16). Further evidence for the existence of a functional mucosal recirculatory route comes from vaccination studies. They unambiguously show that gut-seeking integrin-positive lymphocytes mount the immune response against orally administered antigens, whereas after systemic immunization the immune response is mainly mediated by L-selectin-positive lymphocytes thought to represent peripheral lymph node-seeking cells (15). ABERRANT MIGRATION PATTERNS OF MONONUCLEAR CELLS IN INTESTINAL INFLAMMATION Inflammation induces marked changes both in lymphocyte populations and on the vascular endothelium in the lamina propria. In inflammatory bowel diseases (ulcerative colitis and Crohn s disease), the typical inflammation-induced molecules E-selectin and P- selectin appear on the endothelial cell surface in the absence of appreciable VCAM-1 expression. Perhaps most importantly, many vessels in the lamina propria and follicles, which express low levels of PNAd and VAP-1 under normal conditions, become strongly positive for these two molecules (17). The aberrant expression of PNAd and induction of VAP-1 on inflamed vessels would allow them to support the recruitment of lymphocytes belonging to the peripheral lymph node recirculatory pool into the mucosal sites. The presence in the gut of a cell population that cannot enter mucosal sites from the blood under normal conditions may be fundamental in creating and maintaining some of the pathological features seen in inflammatory bowel diseases. Inflammation and infection at mucosal sites are sometimes followed by extraintestinal manifestations, e.g., reactive arthritis and certain liver diseases. Interconnection of the immune systems of gut and joint has been proposed to be the mechanism for the development of arthritic symptoms subsequent to intestinal inflammation. There are several lines of evidence to support this idea. First, after oral vaccination specific antibody-secreting cells can be found in the synovial tissue, suggesting that these cells or their precursors have selectively homed from mucosal sites to synovial tissues (25). Second, certain cell populations such as E 7 -positive lymphocytes and T cells expressing V 8 receptor are found in the gut and inflamed synovial membrane but not in inflamed skin, whereas cutaneous lymphocyte antigen-positive lymphocytes predominating in the skin are excluded from the gut and synovial membrane (13, 20, 24). Third, mucosal immunoblasts that show efficient binding to mucosal vasculature in the frozen section adhesion assays also bind efficiently to inflamed synovial endothelium but not to peripheral lymph node endothelium. This suggests that cells activated at mucosal sites can enter the inflamed synovial tissue (17). Finally, a rat model of collagen-induced

4 G4 LYMPHOCYTE HOMING TO GUT AND LIVER arthritis shows direct proof that lymphocytes originating from mucosa-associated lymphatic tissues are able to extravasate into the inflamed synovial membrane (21). Despite the dual endothelial-binding specificities of mucosal lymphocytes, 4 7 -integrin does not contribute significantly to mucosal lymphocyte binding to inflamed synovial vasculature probably because its mucosal ligand MAdCAM-1 is not detected on inflamed synovial membrane. The alternative ligand of integrin, VCAM-1, is not very prominent on vascular endothelium in inflamed synovial membrane. However, VAP-1 is strongly expressed in inflamed synovial vasculature, and the binding of mucosal immunoblasts to joint endothelial cells is largely mediated by VAP-1 (5, 16, 19). Thus mucosal lymphocytes use a different but overlapping set of homing-associated molecules to enter inflamed synovial membrane and to extravasate to mucosal sites in physiological conditions. Mucosal macrophages can also leave the mucosal sites and enter the systemic circulation. They may emigrate in a retrograde manner through the vessel wall or be carried via the lymphatics with lymphocytes. P-selectin seems to play a fundamental role in the extravasation of mucosa-derived macrophages into the inflamed synovial membrane, because blocking P- selectin almost abolished their binding to vessels in the inflamed synovial membrane in an in vitro adhesion assay. In addition, E-selectin partially supports the adherence of macrophages to synovial endothelium (19). In the clinical situation, the dual endothelial-binding specificity of mucosal lymphocytes may have adverse consequences. If an infectious agent invades the body through the intestinal surfaces, macrophages may engulf the microbial antigens and carry them to synovial tissues, into which they enter using P-selectin. Expression of P-selectin may be induced on synovial vasculature as a consequence of the systemic effects of inflammation or by direct contact with the microbe-carrying macrophages. Simultaneously, a subpopulation of mucosal lymphocytes is activated by the microbe in Peyer s patches, after which they leave the mucosal sites and enter the circulation. Instead of returning to the mucosa, their intended destination, these activated lymphocytes may enter synovial tissue via the inflammationinduced VAP-1 and other endothelial adhesion molecules. The efficient orchestration of the immune response by these antigen-activated immunoblasts may result in the establishment and maintenance of chronic inflammation in genetically susceptible individuals. It remains to be seen whether a connection similar to that between the gut and the synovial membrane also exists among the gut and the liver and other extraintestinal sites that may become inflamed after intestinal diseases. LYMPHOCYTES IN HUMAN LIVER Normal liver sinusoids contain large granular lymphocytes (pit cells) that are intimately associated with other sinusoidal cells. These cells have natural killer cell activity and enter the liver from the circulation by a process involving adhesion to the sinusoidal endothelium (28). In addition, the normal human liver contains significant numbers of T lymphocytes in the portal tracts and scattered through the parenchyma. It has been suggested that some of these lymphocytes are activated T cells that are removed by the liver and induced to undergo apoptosis. However, in normal human liver relatively few liver-infiltrating lymphocytes express apoptotic markers, and many are presumably patrolling the liver as part of the process of immune surveillance (7). Pathological infiltration of the liver by lymphocytes occurs in response to infectious agents, most notably the hepatitis viruses and in several autoimmune and inflammatory disorders. The distribution of hepatic infiltration can take several forms depending on the inflammatory stimulus. For example, in allograft rejection and primary biliary cirrhosis, lymphocytic infiltration is localized predominantly to the portal tracts, whereas lobular inflammation and infiltration of the parenchyma characterize acute viral hepatitis and autoimmune hepatitis. Thus lymphocytes can enter hepatic tissue by different routes, although the factors that determine the distribution of hepatic infiltration in any given situation are poorly understood (1). The recognition that the hepatic endothelium is heterogeneous with respect to the expression of adhesion molecules begins to provide a molecular explanation for the distinct distribution and composition of lymphocytic infiltration in liver disease. LYMPHOCYTE RECRUITMENT THROUGH THE SINUSOIDS In vivo studies have demonstrated that leukocyte recruitment to the hepatic parenchyma occurs via the sinusoids and involves adhesive interactions with sinusoidal endothelium that is fenestrated and lacks a basement membrane. There is evidence for heterogeneity within the sinusoidal bed, and it is possible that recruitment through the perivenular and periportal sinusoidal endothelium might be differentially regulated (26). The minimal role of endothelial selectins and absence of rolling in sinusoidal vessels in the mouse (29) is consistent with previous human studies reporting a lack of selectin expression on sinusoidal endothelium compared with vascular endothelium in portal tracts and central veins (23). Hepatic sinusoidal endothelium, however, is one of the few endothelial cell types that express VAP-1 constitutively in vivo, and VAP-1 supports adhesion of T cells to human sinusoidal endothelium in noninflamed liver sections (11). Thus VAP-1 might support the initial adhesion of lymphocytes to sinusoidal endothelium before secondary integrinmediated adhesion via ICAM-1 or ICAM-2, both of which are expressed on noninflamed sinusoidal endothelium (23). The expression of endothelial adhesion molecules increases on hepatic sinusoidal endothelium during inflammation, thus broadening the potential molecular

5 LYMPHOCYTE HOMING TO GUT AND LIVER G5 interactions with circulating lymphocytes. The expression of ICAM-1 and LFA-3 is increased, and expression of VCAM-1 and CD31 is induced. In addition, in chronic inflammation sinusoidal endothelium adjacent to areas of active inflammation and fibrosis undergoes the process of capillary formation and expresses CD34 and CD36. The expression of VAP-1, however, remains constant, and the sinusoids are notable for a lack of E-selectin and P-selectin expression even in conditions in which these molecules are induced on adjacent hepatic veins and portal endothelium (2, 23). In the absence of selectins, primary adhesion to activated sinusoidal endothelium could also be mediated by VAP-1 or alternatively via interactions between 4 - integrins and VCAM-1 with subsequent secondary adhesion involving LFA-1 and ICAM-1. Liver-infiltrating T cells express higher levels of very late activation antigen-4 (VLA-4) and LFA-1 compared with peripheral blood T cells, which would support a role for these pathways (1, 8). The lack of MAdCAM-1 expression on hepatic endothelium and the low numbers of lymphocytes positive for 4 7 -integrin in the liver suggest that, in contrast to the gut, 4 7 -integrin plays little role in the liver (5, 8). LYMPHOCYTE INFILTRATION VIA THE PORTAL TRACT Lymphocytes are seen in portal tracts in the normal liver, and infiltration is massively increased in a number of inflammatory disorders. The exact route of entry for lymphocytes into portal tracts is unclear. The portal vessels include hepatic arteries and their portal tract capillaries and portal veins, which do not have classic postcapillary venules but instead empty into the sinusoids (26). During chronic inflammation new microvessels develop in portal tracts (8). These vessels, which are associated with lymphocytic infiltrates, have morphological and phenotypic similarities with the secondary high endothelial venules that have been described in the inflamed synovial membrane, (8) and their development during inflammation is likely to facilitate the recruitment of lymphocytes. In chronic inflammatory conditions, portal vessels express P-selectin, E-selectin, and VCAM-1 (none of which is detected on noninflamed portal endothelium), and high levels of ICAM-1 (8). Assuming that recruitment occurs via a multistep process, the selectins induced on inflamed portal vessels could promote primary adhesion and tethering of lymphocytes with subsequent secondary adhesion occurring via lymphocyte integrins and endothelial VCAM-1 and ICAM-1. We have found expression of RANTES and monocyte chemotactic protein-1 on portal vessels and hepatic veins (but not on sinusoidal endothelium) in normal liver and increased expression of both and induction of mrna for interleukin-8, macrophage inflammatory protein (MIP)-1, and MIP-1 during inflammation (1), suggesting that chemokine synthesis could regulate lymphocyte recruitment to portal tracts. Studies have shown increased expression of both VLA-4 and LFA-1 on lymphocytes infiltrating inflamed portal tracts compared with peripheral blood T cells (8). However, very few lymphocytes in inflamed liver express either L- selectin or selectin ligands (3), arguing against a role for selectins. However, VAP-1 is also expressed on portal vessels and could again play a role in regulating recruitment of lymphocytes to the portal tract. CONCLUSIONS The normal gut and liver can both be regarded as being in a state of controlled inflammation. Vascular endothelium in the lamina propria of the gut and sinusoidal and vascular endothelium of the liver show evidence of low-grade activation based on the expression of inflammation-inducible endothelial adhesion molecules. At both anatomic locations, lymphocyte recruitment is dramatically increased on inflammation. The possibility of blocking of lymphocyte extravasation in vivo has led to competition in designing completely new kinds of antiadhesive drugs against inflammatory disorders. Today these expectations are starting to be fulfilled in animal models. For example, mucosal inflammation in mouse and cotton-top tamarin models can be efficiently alleviated by intravenous administration of monoclonal antibodies against 4 -integrins and MAd- CAM-1 (12, 14). Such studies have encouraged investigators to start pilot studies with monoclonal antibodies and oligosaccharide-based ligand analogs in patients. The results described in this article suggest that blocking of MAdCAM-1, PNAd, and VAP-1 would be of substantial benefit to patients suffering from infections and inflammatory diseases involving inappropriate homing of lymphocytes to the gut. Moreover, blocking of P-selectin and VAP-1 might be beneficial for reducing the synovial homing of gut-derived macrophages and immunoblasts in reactive arthritis. Finally, if VAP-1 is involved in regulating hepatic inflammation it would be an attractive therapeutic target for the selective inhibition of T-cell recruitment to the liver, while leaving other aspects of T-cell function intact. Such a strategy would have great potential, for example, for the development of liver-specific immunosuppression after liver transplantation. Even long-term redirection of lymphocyte homing has had surprisingly little effect on the overall function of the immune defense in either animal or human studies. 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