Direct evidence for activated CD8+ T cell transmigration across portal vein endothelial cells in liver graft rejection

• Published in: Journal of gastroenterology Vol. 51; no. 10; pp. 985 - 998
• Main Authors: Kariya, Taro, Ueta, Hisashi, Xu, Xue-Dong, Koga, Daisuke, Ezaki, Taichi, Yu, Enqiao, Kusumi, Satoshi, Kitazawa, Yusuke, Sawanobori, Yasushi, Ushiki, Tatsuo, Issekutz, Thomas, Matsuno, Kenjiro
• Format: Journal Article
• Language: English
• Published: Tokyo Springer Japan 01.10.2016; Springer; Springer Nature B.V
• Subjects: Abdominal Surgery; Allografts - immunology; Analysis; Animals; Biliary Tract; CD8-Positive T-Lymphocytes - chemistry; CD8-Positive T-Lymphocytes - physiology; Chemokine CXCL10 - analysis; Colorectal Surgery; Endothelium; Endothelium - chemistry; Endothelium - metabolism; Gastroenterology; Graft rejection; Graft Rejection - immunology; Hepatology; Hyaluronan Receptors - analysis; Immunohistochemistry; Integrin alpha4beta1 - metabolism; Integrins; Intercellular Adhesion Molecule-1 - analysis; Intercellular Adhesion Molecule-1 - metabolism; Interleukin-2 Receptor alpha Subunit - analysis; Liver; Liver diseases; Liver Transplantation - adverse effects; Lymphocyte Function-Associated Antigen-1 - metabolism; Male; Medicine; Medicine & Public Health; Microscopy, Electron, Scanning; Original Article—Liver; Original —Liver, Pancreas, and Biliary Tract; Pancreas; Portal Vein; Rats, Inbred ACI; Rats, Inbred Lew; Receptors, CCR5 - analysis; Receptors, CXCR3 - analysis; Surgical Oncology; T cells; Transendothelial and Transepithelial Migration; Transplantation; Up-Regulation; Vascular Cell Adhesion Molecule-1 - metabolism; Transmigration; α4β1 integrin (VLA-4); T-cell; Vascular cell adhesion molecule-1; Portal vein endothelia
• ISSN: 0944-1174; 1435-5922
• DOI: 10.1007/s00535-016-1169-1

Background Lymphocyte 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. Methods A 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. Results The 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 MHCII high cells in the portal tract as well as endothelial walls of PV. Conclusions We 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.