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 PGD2 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 PGD2 to nonmigrated cells. Migration across BVEC or exogenous PGD2 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 PGD2.

Changes in the pattern of plasma extracellular vesicles after severe trauma

“…Confluent cultures were treated for 24h with patient or control plasma EV mixed 1:1 with culture medium including 5U/ml heparin to maintain anticoagulation, with 0 or 5 U/ml tumour necrosis factor-α (TNF) added for the last 4h. A flow-based adhesion assay was performed as described previously [36]. Briefly, ibidi slides were mounted on the stage of a phase-contrast video microscope enclosed in a 37°C perspex chamber.…”

Analysis of the effects of stromal cells on the migration of lymphocytes into and through inflamed tissue using 3-D culture models

“…This suggests that fibroblasts may retain transmigrated T-cells, either because transendothelial migration altered the T-cells or because the fibroblast monolayers became less easy to penetrate when cultured with EC. Notably, our previous studies showed that after migration through EC, T-cells passed more efficiently through monolayers of lymphatic endothelial cells (Ahmed et al, 2011), indicating that their migratory ability is not impaired. Others have reported that dermal fibroblasts isolated from patients with scleroderma promoted mononuclear leukocyte migration through EC cultured on filters (Denton et al, 1998).…”

“…Signals from chemokines (which may vary depending on the inflammatory stimulus) activate the integrins to stabilise the initial interactions (e.g. McGettrick et al, 2009b; Piali et al, 1998), while a downstream signal from prostaglandin D 2 promotes efficient transendothelial migration (Ahmed et al, 2011). …”

Polyunsaturated Fatty Acid-Derived Lipid Mediators and T Cell Function

“…PGD 2 binding to this receptor is also very important for CD4+ T cell trafficking and motility (116, 117). When produced at high concentrations by mast cells, as seen in allergic inflammation, there is a consequent activation and recruitment of Th2 cells toward the PGD 2 producing sites (118, 119).…”