1. Chemoattractant Signals and Adhesion Molecules Promoting Human Regulatory T Cell Recruitment to Porcine Endothelium
- Author
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Rachel Chicheportiche, Jorg Dieter Seebach, Yannick D. Muller, Driss Ehirchiou, Natacha Madelon, Ruhollah Heyrani Nobari, and Mårten K J Schneider
- Subjects
0301 basic medicine ,Cytotoxicity, Immunologic ,Swine ,Cytotoxicity ,T-Lymphocytes ,Cell Communication ,T-Lymphocytes, Regulatory ,Cell Degranulation ,Immune tolerance ,Regulatory/immunology/metabolism ,Chemokine receptor ,0302 clinical medicine ,Immunologic ,Killer Cells ,IL-2 receptor ,Cells, Cultured ,Immunophenotyping/methods ,ddc:616 ,Cultured ,biology ,Cell adhesion molecule ,Chemotaxis ,Intercellular adhesion molecule ,Flow Cytometry ,Cell biology ,Killer Cells, Natural ,Chemotaxis, Leukocyte ,Phenotype ,Heterografts ,Endothelial Cells/immunology/metabolism ,Signal Transduction ,Natural/immunology/metabolism ,Cells ,Integrin ,Immunophenotyping ,03 medical and health sciences ,Cell Adhesion ,Immune Tolerance ,Animals ,Humans ,Cell adhesion ,Cell Adhesion Molecules/immunology/metabolism ,Transplantation ,Transendothelial and Transepithelial Migration ,Endothelial Cells ,Leukocyte ,Chemokine CCL17/immunology/metabolism ,Coculture Techniques ,030104 developmental biology ,biology.protein ,Chemokine CCL17 ,Cell Adhesion Molecules ,030215 immunology - 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.
- Published
- 2016