Abstract
BackgroundLymphocyte recruitment into the portal tract is crucial not only for homeostatic immune surveillance but also for many liver diseases. However, the exact route of entry for lymphocytes into portal tract is still obscure. We investigated this question using a rat hepatic allograft rejection model.MethodsA migration route was analyzed by immunohistological methods including a recently developed scanning electron microscopy method. Transmigration-associated molecules such as selectins, integrins, and chemokines and their receptors expressed by hepatic vessels and recruited T-cells were analyzed by immunohistochemistry and flow cytometry.ResultsThe immunoelectron microscopic analysis clearly showed CD8β+ cells passing through the portal vein (PV) endothelia. Furthermore, the migrating pathway seemed to pass through the endothelial cell body. Local vascular cell adhesion molecule-1 (VCAM-1) expression was induced in PV endothelial cells from day 2 after liver transplantation. Although intercellular adhesion molecule-1 (ICAM-1) expression was also upregulated, it was restricted to sinusoidal endothelia. Recipient T-cells in the graft perfusate were CD25+CD44+ICAM-1+CXCR3+CCR5– and upregulated α4β1 or αLβ2 integrins. Immunohistochemistry showed the expression of CXCL10 in donor MHCIIhigh cells in the portal tract as well as endothelial walls of PV.ConclusionsWe show for the first time direct evidence of T-cell transmigration across PV endothelial cells during hepatic allograft rejection. Interactions between VCAM-1 on endothelia and α4β1 integrin on recipient effector T-cells putatively play critical roles in adhesion and transmigration through endothelia. A chemokine axis of CXCL10 and CXCR3 also may be involved.Electronic supplementary materialThe online version of this article (doi:10.1007/s00535-016-1169-1) contains supplementary material, which is available to authorized users.
Highlights
Immunosurveillance is conducted by recirculating lymphocytes and dendritic cells (DCs) [1]
Local vascular cell adhesion molecule-1 (VCAM-1) expression was induced in portal vein (PV) endothelial cells from day 2 after liver transplantation
Immunohistochemistry showed the expression of CXCL10 in donor MHCIIhigh cells in the portal tract as well as endothelial walls of PV
Summary
Immunosurveillance is conducted by recirculating lymphocytes and dendritic cells (DCs) [1]. The liver is constantly subjected to antigen exposure in the portal venous blood derived from the gastrointestinal tract To inspect these antigens, the liver is equipped with two distinct types of defense. The liver is extensively surveyed by these immunocompetent cells and their trafficking would be further enhanced, if inflammatory stimuli persisted in the liver in order to develop adaptive immune responses In this respect, the portal tract have been considered as a central site for adaptive immune response of the liver diseases and identified as massive leukocyte accumulation sites in many types of liver disease such as hepatitis [4], infection [5], and transplant rejection [6].
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