title: CMV infection of human sinusoidal endothelium regulates hepatic T cell recruitment and activation.
abstract: OBJECTIVE
  Human cytomegalovirus infection (HCMV) is associated with an increased morbidity after liver transplantation, by facilitating allograft rejection and accelerating underlying hepatic inflammation. We hypothesized that human hepatic sinusoidal endothelial cells infected with HCMV possess the capacity to modulate allogeneic T cell recruitment and activation, thereby providing a plausible mechanism of how HCMV infection is able to enhance hepatic immune activation.
  
  
  METHODS
  Human hepatic sinusoidal endothelial cells were isolated from explanted livers and infected with recombinant endotheliotropic HCMV. We used static and flow-based models to quantify adhesion and transendothelial migration of allogeneic T cell subsets and determine their post-migratory phenotype and function.
  
  
  RESULTS
  HCMV infection of primary human hepatic sinusoidal endothelial cells facilitated ICAM-1 and CXCL10-dependent CD4 T cell transendothelial migration under physiological levels of shear stress. Recruited T cells were primarily non-virus-specific CXCR3(hi) effector memory T cells, which demonstrated features of LFA3-dependent Th1 activation after migration, and activated regulatory T cells, which retained a suppressive phenotype following transmigration.
  
  
  CONCLUSIONS
  The ability of infected hepatic endothelium to recruit distinct functional CD4 T cell subsets shows how HCMV facilitates hepatic inflammation and immune activation and may simultaneously favor virus persistence.
authors.affiliation: NIHR Biomedical Research Unit and Centre for Liver Research, University of Birmingham, Birmingham, United Kingdom; Department of Internal Medicine IV, Jena University Hospital, Friedrich Schiller University of Jena, Jena, Germany; Center for Sepsis Control and Care, Jena University Hospital, Friedrich Schiller University of Jena, Jena, Germany. Electronic address: tony.bruns@med.uni-jena.de.
authors.forename: Tony
authors.initials: T
authors.lastname: Bruns
authors.affiliation: NIHR Biomedical Research Unit and Centre for Liver Research, University of Birmingham, Birmingham, United Kingdom; Department of Medicine III, University Hospital Aachen, RWTH Aachen University, Aachen, Germany.
authors.forename: Henning W
authors.initials: HW
authors.lastname: Zimmermann
authors.affiliation: School of Cancer Sciences, University of Birmingham, Birmingham, United Kingdom.
authors.forename: Annette
authors.initials: A
authors.lastname: Pachnio
authors.affiliation: NIHR Biomedical Research Unit and Centre for Liver Research, University of Birmingham, Birmingham, United Kingdom.
authors.forename: Ka-Kit
authors.initials: KK
authors.lastname: Li
authors.affiliation: NIHR Biomedical Research Unit and Centre for Liver Research, University of Birmingham, Birmingham, United Kingdom.
authors.forename: Palak J
authors.initials: PJ
authors.lastname: Trivedi
authors.affiliation: NIHR Biomedical Research Unit and Centre for Liver Research, University of Birmingham, Birmingham, United Kingdom; Department of Cellular Pathology, Queen Elizabeth Hospital Birmingham, Birmingham, United Kingdom.
authors.forename: Gary
authors.initials: G
authors.lastname: Reynolds
authors.affiliation: NIHR Biomedical Research Unit and Centre for Liver Research, University of Birmingham, Birmingham, United Kingdom; Department of Cellular Pathology, Queen Elizabeth Hospital Birmingham, Birmingham, United Kingdom.
authors.forename: Stefan
authors.initials: S
authors.lastname: Hubscher
authors.affiliation: NIHR Biomedical Research Unit and Centre for Liver Research, University of Birmingham, Birmingham, United Kingdom.
authors.forename: Zania
authors.initials: Z
authors.lastname: Stamataki
authors.affiliation: School of Immunity and Infection, University of Birmingham, Birmingham, United Kingdom.
authors.forename: Paul W
authors.initials: PW
authors.lastname: Badenhorst
authors.affiliation: NIHR Biomedical Research Unit and Centre for Liver Research, University of Birmingham, Birmingham, United Kingdom.
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Weston
authors.affiliation: School of Cancer Sciences, University of Birmingham, Birmingham, United Kingdom.
authors.forename: Paul A
authors.initials: PA
authors.lastname: Moss
authors.affiliation: NIHR Biomedical Research Unit and Centre for Liver Research, University of Birmingham, Birmingham, United Kingdom. Electronic address: d.h.adams@bham.ac.uk.
authors.forename: David H
authors.initials: DH
authors.lastname: Adams
mesh_terms: D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism*; D002448:Cell Adhesion; D002465:Cell Movement; D002478:Cells, Cultured; D003587:Cytomegalovirus; D003586:Cytomegalovirus Infections / Q000276:immunology* / Q000473:pathology / Q000821:virology; D004730:Endothelium, Vascular / Q000378:metabolism* / Q000473:pathology / Q000821:virology; D006801:Humans; D007111:Immunity, Cellular; D008099:Liver / Q000276:immunology* / Q000378:metabolism / Q000821:virology
keywords: Cytomegalovirus; Liver immunology; Liver sinusoidal endothelial cells; Transendothelial migration