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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).

Original publication

DOI

10.4049/jimmunol.1100299

Type

Journal article

Journal

J immunol

Publication Date

01/08/2011

Volume

187

Pages

1432 - 1439

Keywords

CD4-Positive T-Lymphocytes, CD8-Positive T-Lymphocytes, Cell Adhesion, Cell Movement, Cell Separation, Cells, Cultured, Chemokine CCL21, Endothelium, Lymphatic, Endothelium, Vascular, Humans, Immunologic Memory, Immunologic Surveillance, Inflammation Mediators, Interferons, Lymphocyte Activation, Prostaglandin D2, Receptors, CCR7, Receptors, CXCR3, Signal Transduction, Tumor Necrosis Factor-alpha