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Vascular adhesion protein 1 (VAP-1) mediates lymphocyte subtype-specific, selectin-independent recognition of vascular endothelium in human lymph nodes.

Salmi M, Tohka S, Berg EL, Butcher EC, Jalkanen S - J. Exp. Med. (1997)

Bottom Line: Distinct subsets of mononuclear cells bind to high endothelial venules (HEVs) in different lymphoid organs to a different extent, but the molecular mechanisms behind this selectivity have remained poorly characterized.Finally, intravital microscopy revealed that VAP-1 is involved in initial interactions between human lymphocytes and endothelial cells in inflamed rabbit mesenterial venules in vivo.In conclusion, VAP-1 is a novel contact-initiating ligand that discriminates between different subpopulations of mononuclear cells and is an appealing target for selective modulation of adhesion of CD8- and CD16-positive effector cells.

View Article: PubMed Central - PubMed

Affiliation: National Public Health Institute, and MediCity Research Laboratory, Turku University, 20520 Turku, Finland. marko.salmi@utu.fi

ABSTRACT
Interactions between lymphocyte surface receptors and their ligands on vascular endothelial cells regulate the exit of lymphocytes from the circulation. Distinct subsets of mononuclear cells bind to high endothelial venules (HEVs) in different lymphoid organs to a different extent, but the molecular mechanisms behind this selectivity have remained poorly characterized. Here we show that vascular adhesion protein-1 (VAP-1) mediates subtype-specific binding of CD8-positive T cells and natural killer cells to human endothelium. VAP-1-dependent, oligosaccharide-dependent peripheral lymph node (PLN) HEV adhesion under shear was independent of L-selectin, P-selectin glycoprotein ligand 1, and alpha4 integrins, the known lymphocyte receptors involved in the initial recognition of endothelial cells. PLN HEV adhesion was also critically dependent on peripheral lymph node vascular addressins (PNAds), but lymphocyte L-selectin was absolutely required for PNAd binding. Most lymphocytes relied on both PNAd and VAP-1 in HEV binding. The overlapping function of L-selectin ligands and VAP-1 in PLN introduces a new control point into the lymphocyte extravasation process. Finally, intravital microscopy revealed that VAP-1 is involved in initial interactions between human lymphocytes and endothelial cells in inflamed rabbit mesenterial venules in vivo. In conclusion, VAP-1 is a novel contact-initiating ligand that discriminates between different subpopulations of mononuclear cells and is an appealing target for selective modulation of adhesion of CD8- and CD16-positive effector cells.

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Most PBL use both  PNAd and VAP-1 in PLN HEV  binding. PBL were treated with  anti–L-selectin mAb and PLNs  with mAbs against different endothelial adhesion molecules  alone or in combination, and the  HEV adherence was determined.
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Figure 6: Most PBL use both PNAd and VAP-1 in PLN HEV binding. PBL were treated with anti–L-selectin mAb and PLNs with mAbs against different endothelial adhesion molecules alone or in combination, and the HEV adherence was determined.

Mentions: Next we wanted to see whether VAP-1 and PNAd represent two distinct adhesion routes to PLN HEVs. Binding of normal PBL, which contain 50–80% L-selectin positive cells, to PLN HEVs was reduced by ∼75% with separate anti-PNAd, anti–L-selectin, and anti–VAP-1 treatments in these assays (Fig. 6). In contrast, E-selectin, P-selectin, and VCAM-1 played no role in PBL binding to normal PLN. When the function of both VAP-1 and PNAd was blocked, we observed ∼10% more inhibition of HEV binding when compared to sections pretreated with mAb MECA-79 only. This additive inhibition was seen in every experiment performed, but it failed to reach statistical significance (P = 0.07 when comparing MECA-79 pretreatment to combined MECA-79 and 1B2 pretreatment). These data indicate that most PBL use both VAP-1 and PNAd to bind to PLN HEVs, but also reveal that a small PBL subpopulation may rely exclusively on VAP-1. L-selectin was also important for PLN HEV adhesion of CD8-positive PBL (Fig. 7). In support of additional inhibition of total PBL binding to PLN HEVs seen by combined blocking of PNAd and VAP-1, combined blocking of both L-selectin and VAP-1 also produced more marked inhibition in PLN HEV adhesion of CD8-positive PBL than blocking of either adhesion molecule separately.


Vascular adhesion protein 1 (VAP-1) mediates lymphocyte subtype-specific, selectin-independent recognition of vascular endothelium in human lymph nodes.

Salmi M, Tohka S, Berg EL, Butcher EC, Jalkanen S - J. Exp. Med. (1997)

Most PBL use both  PNAd and VAP-1 in PLN HEV  binding. PBL were treated with  anti–L-selectin mAb and PLNs  with mAbs against different endothelial adhesion molecules  alone or in combination, and the  HEV adherence was determined.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2199032&req=5

Figure 6: Most PBL use both PNAd and VAP-1 in PLN HEV binding. PBL were treated with anti–L-selectin mAb and PLNs with mAbs against different endothelial adhesion molecules alone or in combination, and the HEV adherence was determined.
Mentions: Next we wanted to see whether VAP-1 and PNAd represent two distinct adhesion routes to PLN HEVs. Binding of normal PBL, which contain 50–80% L-selectin positive cells, to PLN HEVs was reduced by ∼75% with separate anti-PNAd, anti–L-selectin, and anti–VAP-1 treatments in these assays (Fig. 6). In contrast, E-selectin, P-selectin, and VCAM-1 played no role in PBL binding to normal PLN. When the function of both VAP-1 and PNAd was blocked, we observed ∼10% more inhibition of HEV binding when compared to sections pretreated with mAb MECA-79 only. This additive inhibition was seen in every experiment performed, but it failed to reach statistical significance (P = 0.07 when comparing MECA-79 pretreatment to combined MECA-79 and 1B2 pretreatment). These data indicate that most PBL use both VAP-1 and PNAd to bind to PLN HEVs, but also reveal that a small PBL subpopulation may rely exclusively on VAP-1. L-selectin was also important for PLN HEV adhesion of CD8-positive PBL (Fig. 7). In support of additional inhibition of total PBL binding to PLN HEVs seen by combined blocking of PNAd and VAP-1, combined blocking of both L-selectin and VAP-1 also produced more marked inhibition in PLN HEV adhesion of CD8-positive PBL than blocking of either adhesion molecule separately.

Bottom Line: Distinct subsets of mononuclear cells bind to high endothelial venules (HEVs) in different lymphoid organs to a different extent, but the molecular mechanisms behind this selectivity have remained poorly characterized.Finally, intravital microscopy revealed that VAP-1 is involved in initial interactions between human lymphocytes and endothelial cells in inflamed rabbit mesenterial venules in vivo.In conclusion, VAP-1 is a novel contact-initiating ligand that discriminates between different subpopulations of mononuclear cells and is an appealing target for selective modulation of adhesion of CD8- and CD16-positive effector cells.

View Article: PubMed Central - PubMed

Affiliation: National Public Health Institute, and MediCity Research Laboratory, Turku University, 20520 Turku, Finland. marko.salmi@utu.fi

ABSTRACT
Interactions between lymphocyte surface receptors and their ligands on vascular endothelial cells regulate the exit of lymphocytes from the circulation. Distinct subsets of mononuclear cells bind to high endothelial venules (HEVs) in different lymphoid organs to a different extent, but the molecular mechanisms behind this selectivity have remained poorly characterized. Here we show that vascular adhesion protein-1 (VAP-1) mediates subtype-specific binding of CD8-positive T cells and natural killer cells to human endothelium. VAP-1-dependent, oligosaccharide-dependent peripheral lymph node (PLN) HEV adhesion under shear was independent of L-selectin, P-selectin glycoprotein ligand 1, and alpha4 integrins, the known lymphocyte receptors involved in the initial recognition of endothelial cells. PLN HEV adhesion was also critically dependent on peripheral lymph node vascular addressins (PNAds), but lymphocyte L-selectin was absolutely required for PNAd binding. Most lymphocytes relied on both PNAd and VAP-1 in HEV binding. The overlapping function of L-selectin ligands and VAP-1 in PLN introduces a new control point into the lymphocyte extravasation process. Finally, intravital microscopy revealed that VAP-1 is involved in initial interactions between human lymphocytes and endothelial cells in inflamed rabbit mesenterial venules in vivo. In conclusion, VAP-1 is a novel contact-initiating ligand that discriminates between different subpopulations of mononuclear cells and is an appealing target for selective modulation of adhesion of CD8- and CD16-positive effector cells.

Show MeSH
Related in: MedlinePlus