title: Chemoattractant Signals and Adhesion Molecules Promoting Human Regulatory T Cell Recruitment to Porcine Endothelium.
abstract: BACKGROUND
  Human CD4+CD25+Foxp3+ T regulatory cells (huTreg) suppress CD4+ T cell-mediated antipig xenogeneic responses in vitro and might therefore be used to induce xenograft tolerance. The present study investigated the role of the adhesion molecules, their porcine ligands, and the chemoattractant factors that may promote the recruitment of huTreg to porcine aortic endothelial cells (PAEC) and their capacity to regulate antiporcine natural killer (NK) cell responses.
  
  
  METHODS
  Interactions between ex vivo expanded huTreg and PAEC were studied by static chemotaxis assays and flow-based adhesion and transmigration assays. In addition, the suppressive function of huTreg on human antiporcine NK cell responses was analyzed.
  
  
  RESULTS
  The TNFα-activated PAEC released factors that induce huTreg chemotaxis, partially inhibited by antihuman CXCR3 blocking antibodies. Coating of PAEC with human CCL17 significantly increased the transmigration of CCR4+ huTreg under physiological shear stress. Under static conditions, transendothelial Treg migration was inhibited by blocking integrin sub-units (CD18, CD49d) on huTreg, or their respective porcine ligands intercellular adhesion molecule 2 (CD102) and vascular cell adhesion molecule 1 (CD106). Finally, huTreg partially suppressed xenogeneic human NK cell adhesion, NK cytotoxicity and degranulation (CD107 expression) against PAEC; however, this inhibition was modest, and there was no significant change in the production of IFNγ.
  
  
  CONCLUSIONS
  Recruitment of huTreg to porcine endothelium depends on particular chemokine receptors (CXCR3, CCR4) and integrins (CD18 and CD49d) and was increased by CCL17 coating. These results will help to develop new strategies to enhance the recruitment of host huTreg to xenogeneic grafts to regulate cell-mediated xenograft rejection including NK cell responses.
authors.affiliation: 1 Laboratory of Transplantation Immunology, Division of Immunology and Allergology, Department of Medicine Specialties, Medical Faculty and University Hospital Geneva, Geneva, Switzerland. 2 Laboratory of Vascular Immunology, University Hospital Zurich, Zurich, Switzerland.
authors.forename: Driss
authors.initials: D
authors.lastname: Ehirchiou
authors.forename: Yannick D
authors.initials: YD
authors.lastname: Muller
authors.forename: Rachel
authors.initials: R
authors.lastname: Chicheportiche
authors.forename: Ruhollah
authors.initials: R
authors.lastname: Heyrani Nobari
authors.forename: Natacha
authors.initials: N
authors.lastname: Madelon
authors.forename: Mårten K J
authors.initials: MK
authors.lastname: Schneider
authors.forename: Jörg D
authors.initials: JD
authors.lastname: Seebach
mesh_terms: D000818:Animals; D002448:Cell Adhesion; D015815:Cell Adhesion Molecules / Q000276:immunology / Q000378:metabolism*; D002450:Cell Communication; D015550:Cell Degranulation; D002478:Cells, Cultured; D054414:Chemokine CCL17 / Q000276:immunology / Q000378:metabolism*; D002634:Chemotaxis, Leukocyte; D018920:Coculture Techniques; D003602:Cytotoxicity, Immunologic; D042783:Endothelial Cells / Q000276:immunology / Q000378:metabolism*; D005434:Flow Cytometry; D064593:Heterografts; D006801:Humans; D007108:Immune Tolerance; D016130:Immunophenotyping / Q000379:methods; D007694:Killer Cells, Natural / Q000276:immunology / Q000378:metabolism*; D010641:Phenotype; D015398:Signal Transduction; D013552:Swine; D050378:T-Lymphocytes, Regulatory / Q000276:immunology / Q000378:metabolism*; D057705:Transendothelial and Transepithelial Migration
chemical_list: C106230:CCL17 protein, human; D015815:Cell Adhesion Molecules; D054414:Chemokine CCL17