title: Prostaglandin D2 regulates CD4+ memory T cell trafficking across blood vascular endothelium and primes these cells for clearance across lymphatic endothelium.
abstract: Memory lymphocytes support inflammatory and immune responses. To do this, they enter tissue via blood vascular endothelial cells (BVEC) and leave tissue via lymphatic vascular endothelial cells (LVEC). In this study, we describe a hierarchy of signals, including novel regulatory steps, which direct the sequential migration of human T cells across the blood and the lymphatic EC. Cytokine-stimulated (TNF and IFN) human BVEC preferentially recruited memory T cells from purified PBL. Lymphocyte recruitment from flow could be blocked using a function-neutralizing Ab against CXCR3. However, a receptor antagonist directed against the PGD(2) receptor DP2 (formerly chemoattractant receptor-homologous molecule expressed on Th2 cells) inhibited transendothelial migration, demonstrating that the sequential delivery of the chemokine and prostanoid signals was required for efficient lymphocyte recruitment. CD4(+) T cells recruited by BVEC migrated with significantly greater efficiency across a second barrier of human LVEC, an effect reproduced by the addition of exogenous PGD(2) to nonmigrated cells. Migration across BVEC or exogenous PGD(2) modified the function, but not the expression, of CCR7, so that chemotaxis toward CCL21 was significantly enhanced. Thus, chemokines may not regulate all stages of lymphocyte migration during inflammation, and paradigms describing their trafficking may need to account for the role of PGD(2).
authors.affiliation: School of Clinical and Experimental Medicine, Medical School, University of Birmingham, Birmingham B15 2TT, United Kingdom.
authors.forename: S Rumel
authors.initials: SR
authors.lastname: Ahmed
authors.forename: Helen M
authors.initials: HM
authors.lastname: McGettrick
authors.forename: Clara M
authors.initials: CM
authors.lastname: Yates
authors.forename: Christopher D
authors.initials: CD
authors.lastname: Buckley
authors.forename: Marianne J
authors.initials: MJ
authors.lastname: Ratcliffe
authors.forename: Gerard B
authors.initials: GB
authors.lastname: Nash
authors.forename: G Ed
authors.initials: GE
authors.lastname: Rainger
mesh_terms: D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D002448:Cell Adhesion / Q000276:immunology; D002465:Cell Movement / Q000276:immunology*; D002469:Cell Separation; D002478:Cells, Cultured; D054421:Chemokine CCL21 / Q000502:physiology; D004729:Endothelium, Lymphatic / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D004730:Endothelium, Vascular / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D007156:Immunologic Memory; D007157:Immunologic Surveillance / Q000276:immunology; D018836:Inflammation Mediators / Q000097:blood / Q000502:physiology; D007372:Interferons / Q000502:physiology; D008213:Lymphocyte Activation / Q000276:immunology*; D015230:Prostaglandin D2 / Q000502:physiology*; D054400:Receptors, CCR7 / Q000502:physiology; D054367:Receptors, CXCR3 / Q000097:blood; D015398:Signal Transduction / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology
chemical_list: C515478:CCL21 protein, human; C515370:CCR7 protein, human; C515187:CXCR3 protein, human; D054421:Chemokine CCL21; D018836:Inflammation Mediators; D054400:Receptors, CCR7; D054367:Receptors, CXCR3; D014409:Tumor Necrosis Factor-alpha; D007372:Interferons; D015230:Prostaglandin D2