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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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VAP-1 does not recognize L-selectin. (A) Expression of human L-selectin  on mouse L1-2 L-selectin transfectants. (B) L1-2 L-selectin transfectants (dark blue spots)  efficiently bind to human PLN HEVs (seven different-sized HEV, one outlined by a  dashed line, can be seen as light blue structures). (C) L1-2 L-selectin transfectant binding  to HEV in human PLNs is independent of VAP-1. Transfectants were pretreated with  Dreg-56 and PLN tissue with 1B2 and/or MECA-79, and the HEV adhesion was determined. (D) L-selectin chimera binds PNAd, but not VAP-1. The Ig-chimeras were used  to deplete tonsil lysate and the nonprecipitated molecules were analyzed using immunoblotting and the mAbs indicated.
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Figure 4: VAP-1 does not recognize L-selectin. (A) Expression of human L-selectin on mouse L1-2 L-selectin transfectants. (B) L1-2 L-selectin transfectants (dark blue spots) efficiently bind to human PLN HEVs (seven different-sized HEV, one outlined by a dashed line, can be seen as light blue structures). (C) L1-2 L-selectin transfectant binding to HEV in human PLNs is independent of VAP-1. Transfectants were pretreated with Dreg-56 and PLN tissue with 1B2 and/or MECA-79, and the HEV adhesion was determined. (D) L-selectin chimera binds PNAd, but not VAP-1. The Ig-chimeras were used to deplete tonsil lysate and the nonprecipitated molecules were analyzed using immunoblotting and the mAbs indicated.

Mentions: Binding of an immunomagnetically separated L-selectin– positive subpopulation of PBL to PLNs was also efficiently blocked by mAb 1B2 pretreatment (Fig. 3 C). Therefore, we determined whether L-selectin, although not necessary for lymphocyte binding to VAP-1, can also function as a receptor of VAP-1. The high level of surface expression of human L-selectin on mouse pre–B cell lymphoma L1-2 transfectants (Fig. 4 A) was enough to confer on these transfectants a strong ability to bind to human PLN HEVs (Fig. 4 B). This adherence was completely inhibitable by anti–L-selectin mAb Dreg-56 pretreatment of lymphocytes and >70% was also abrogated by mAb MECA-79 pretreatment of the endothelial cells (Fig. 4 C). In contrast, the binding of L-selectin transfectants was completely unaffected by mAb 1B2 treatment (Fig. 4 C). Hence, L-selectin expression is sufficient to mediate binding of lymphoma cells to PLN HEVs, but this binding is entirely independent of VAP-1 function.


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)

VAP-1 does not recognize L-selectin. (A) Expression of human L-selectin  on mouse L1-2 L-selectin transfectants. (B) L1-2 L-selectin transfectants (dark blue spots)  efficiently bind to human PLN HEVs (seven different-sized HEV, one outlined by a  dashed line, can be seen as light blue structures). (C) L1-2 L-selectin transfectant binding  to HEV in human PLNs is independent of VAP-1. Transfectants were pretreated with  Dreg-56 and PLN tissue with 1B2 and/or MECA-79, and the HEV adhesion was determined. (D) L-selectin chimera binds PNAd, but not VAP-1. The Ig-chimeras were used  to deplete tonsil lysate and the nonprecipitated molecules were analyzed using immunoblotting and the mAbs indicated.
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Related In: Results  -  Collection

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

Figure 4: VAP-1 does not recognize L-selectin. (A) Expression of human L-selectin on mouse L1-2 L-selectin transfectants. (B) L1-2 L-selectin transfectants (dark blue spots) efficiently bind to human PLN HEVs (seven different-sized HEV, one outlined by a dashed line, can be seen as light blue structures). (C) L1-2 L-selectin transfectant binding to HEV in human PLNs is independent of VAP-1. Transfectants were pretreated with Dreg-56 and PLN tissue with 1B2 and/or MECA-79, and the HEV adhesion was determined. (D) L-selectin chimera binds PNAd, but not VAP-1. The Ig-chimeras were used to deplete tonsil lysate and the nonprecipitated molecules were analyzed using immunoblotting and the mAbs indicated.
Mentions: Binding of an immunomagnetically separated L-selectin– positive subpopulation of PBL to PLNs was also efficiently blocked by mAb 1B2 pretreatment (Fig. 3 C). Therefore, we determined whether L-selectin, although not necessary for lymphocyte binding to VAP-1, can also function as a receptor of VAP-1. The high level of surface expression of human L-selectin on mouse pre–B cell lymphoma L1-2 transfectants (Fig. 4 A) was enough to confer on these transfectants a strong ability to bind to human PLN HEVs (Fig. 4 B). This adherence was completely inhibitable by anti–L-selectin mAb Dreg-56 pretreatment of lymphocytes and >70% was also abrogated by mAb MECA-79 pretreatment of the endothelial cells (Fig. 4 C). In contrast, the binding of L-selectin transfectants was completely unaffected by mAb 1B2 treatment (Fig. 4 C). Hence, L-selectin expression is sufficient to mediate binding of lymphoma cells to PLN HEVs, but this binding is entirely independent of VAP-1 function.

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