Allister J. Grant

Primary sclerosing cholangitis (PSC), a chronic inflammatory liver disease characterized by progressive bile duct destruction, develops as an extra-intestinal complication of inflammatory bowel disease (IBD) (Chapman, R.W. 1991. Gut. 32:1433-1435). However, the liver and bowel inflammation are rarely concomitant, and PSC can develop in patients whose colons have been removed previously. We hypothesized that PSC is mediated by long-lived memory T cells originally activated in the gut, but able to mediate extra-intestinal inflammation in the absence of active IBD (Grant, A.J., P.F. Lalor, M. Salmi, S. Jalkanen, and D.H. Adams. 2002. Lancet. 359:150-157). In support of this, we show that liver-infiltrating lymphocytes in PSC include mucosal T cells recruited to the liver by aberrant expression of the gut-specific chemokine CCL25 that activates alpha4beta7 binding to mucosal addressin cell adhesion molecule 1 on the hepatic endothelium. This is the first demonstration in humans that T cells activated in the gut can be recruited to an extra-intestinal site of disease and provides a paradigm to explain the pathogenesis of extra-intestinal complications of IBD.

Mucosal addressin cell adhesion molecule (MAdCAM-1) plays a pivotal role in T-lymphocyte homing to the gut. Given the strong association between the autoimmune liver diseases primary sclerosing cholangitis and autoimmune hepatitis and inflammatory bowel disease, we investigated the role of MAdCAM-1 in recruiting mucosal lymphocytes to the liver. MAdCAM-1 was strongly expressed on inflamed portal vein/sinusoidal endothelium in autoimmune mediated liver disease. In modified Stamper-Woodruff assays, MAdCAM-1 on hepatic vessels supported adhesion of alpha4beta7+ lymphocytes (i.e., gut-derived T cells) from patients with inflammatory bowel disease and primary sclerosing cholangitis. This adhesion was inhibited by pretreatment with blocking antibodies to MAdCAM-1, alpha4beta7, or the integrin alpha4 chain indicating that MAdCAM-1 in inflamed liver is functionally active. Circulating lymphocytes from patients with primary sclerosing cholangitis showed rolling adhesion on MAdCAM-1 transfectants in a flow-based adhesion assay that could be blocked by anti-MAdCAM-1 or anti-alpha4beta7 mAbs. These findings indicate that, under certain circumstances, vessels in the human liver support adhesion of alpha4beta7+ mucosal lymphocytes via binding to aberrantly expressed MAdCAM-1 on liver endothelium. This provides a mechanism to explain the hepatic recruitment of mucosal lymphocytes in inflammatory liver disease complicating inflammatory bowel disease.

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-1alpha (MIP-1alpha), interferon gamma 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.

Mucosal tissues require constant immune surveillance to clear harmful pathogens while maintaining tolerance to self Ags. Regulatory T cells (Tregs) play a central role in this process and expression of alpha(E)beta(7) has been reported to define a subset of Tregs with tropism for inflamed tissues. However, the signals responsible for recruiting Tregs to epithelial surfaces are poorly understood. We have isolated a subset of CCR10-expressing CD25+CD4+Foxp3+ Tregs with potent anti-inflammatory properties from chronically inflamed human liver. The CCR10+ Tregs were detected around bile ducts that expressed increased levels of the CCR10 ligand CCL28. CCL28 was secreted by primary human cholangiocytes in vitro in response to LPS, IL-1beta, or bile acids. Exposure of CCR10+ Tregs to CCL28 in vitro stimulated migration and adhesion to mucosal addressin cell adhesion molecule-1 and VCAM-1. Liver-derived CCR10+ Tregs expressed low levels of CCR7 but high levels of CXCR3, a chemokine receptor associated with infiltration into inflamed tissue and contained a subset of alpha(E)beta7(+) cells. We propose that CXCR3 promotes the recruitment of Tregs to inflamed tissues and CCR10 allows them to respond to CCL28 secreted by epithelial cells resulting in the accumulation of CCR10+ Tregs at mucosal surfaces.