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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 binds to a  novel contact initiating lymphocyte counterreceptor. PBL were  treated with the indicated mAbs  (HP2/1 and PL1) against lymphocyte adhesion receptors or  with O-sialoglycoprotease (O-sgp),  and their binding to the target  tissue treated with anti–VAP-1  or control mAbs was evaluated.  Binding of PBL treated with  anti–α4 integrin mAb was tested  to PLN HEVs, whereas binding  of PBL pretreated with anti– PSGL-1 mAb and O-sgp was  evaluated using tonsil as a target  tissue.
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Figure 5: VAP-1 binds to a novel contact initiating lymphocyte counterreceptor. PBL were treated with the indicated mAbs (HP2/1 and PL1) against lymphocyte adhesion receptors or with O-sialoglycoprotease (O-sgp), and their binding to the target tissue treated with anti–VAP-1 or control mAbs was evaluated. Binding of PBL treated with anti–α4 integrin mAb was tested to PLN HEVs, whereas binding of PBL pretreated with anti– PSGL-1 mAb and O-sgp was evaluated using tonsil as a target tissue.

Mentions: In addition to L-selectin, α4 integrins and PSGL-1 can mediate tethering and rolling of lymphocytes on vascular endothelium or isolated endothelial ligands (28, 33–36). To address whether α4 integrins can function as lymphocyte ligands of VAP-1, we analyzed the role of α4 integrin in PLN HEV adhesion of L-selectin–negative PBL (Fig. 5). A function-inhibiting anti-α4 mAb, HP2/1, which detects both α4β1 and α4β7 heterodimers, had no effect on adherence of these cells to HEVs under rotatory conditions. Moreover, mAb 1B2 still efficiently inhibited PLN HEV adhesion of α4-blocked PBL, indicating that functional α4 is not needed to support VAP-1–dependent binding. VAP-1 function was independent of the lymphocyte PSGL-1 as well. When PBL were pretreated with a function-blocking anti–PSGL-1 mAb PL1, ∼10% inhibition in lymphocyte binding to tonsil HEV was seen. When the anti–PSGL-1 mAb–treated PBL were added to anti–VAP-1 mAb–treated tonsil sections, 10% additive inhibitory effect on the adhesion was seen when compared to the effect of the anti– VAP-1 mAb alone. To assess the role of other sialomucins as potential counterreceptors for VAP-1, we treated lymphocytes with the sialomucin-degrading enzyme O-sialoglycoprotease, and then analyzed the VAP-1 dependence of their tonsil HEV binding. This treatment had a marginal effect on PBL adhesion to HEV, but the binding of O-sialoglycoprotease–treated cells was still efficiently blocked by mAb 1B2 pretreatment of the target tissue indicating that an O-sialoglycoprotease–sensitive molecule is not at least the principal lymphocyte ligand of VAP-1. Thus, none of the currently known lymphocyte adhesion molecules (L-selectin, α4 integrins, or PSGL-1) mediating rolling on endothelial cells are receptors for VAP-1.


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 binds to a  novel contact initiating lymphocyte counterreceptor. PBL were  treated with the indicated mAbs  (HP2/1 and PL1) against lymphocyte adhesion receptors or  with O-sialoglycoprotease (O-sgp),  and their binding to the target  tissue treated with anti–VAP-1  or control mAbs was evaluated.  Binding of PBL treated with  anti–α4 integrin mAb was tested  to PLN HEVs, whereas binding  of PBL pretreated with anti– PSGL-1 mAb and O-sgp was  evaluated using tonsil as a target  tissue.
© Copyright Policy
Related In: Results  -  Collection

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

Figure 5: VAP-1 binds to a novel contact initiating lymphocyte counterreceptor. PBL were treated with the indicated mAbs (HP2/1 and PL1) against lymphocyte adhesion receptors or with O-sialoglycoprotease (O-sgp), and their binding to the target tissue treated with anti–VAP-1 or control mAbs was evaluated. Binding of PBL treated with anti–α4 integrin mAb was tested to PLN HEVs, whereas binding of PBL pretreated with anti– PSGL-1 mAb and O-sgp was evaluated using tonsil as a target tissue.
Mentions: In addition to L-selectin, α4 integrins and PSGL-1 can mediate tethering and rolling of lymphocytes on vascular endothelium or isolated endothelial ligands (28, 33–36). To address whether α4 integrins can function as lymphocyte ligands of VAP-1, we analyzed the role of α4 integrin in PLN HEV adhesion of L-selectin–negative PBL (Fig. 5). A function-inhibiting anti-α4 mAb, HP2/1, which detects both α4β1 and α4β7 heterodimers, had no effect on adherence of these cells to HEVs under rotatory conditions. Moreover, mAb 1B2 still efficiently inhibited PLN HEV adhesion of α4-blocked PBL, indicating that functional α4 is not needed to support VAP-1–dependent binding. VAP-1 function was independent of the lymphocyte PSGL-1 as well. When PBL were pretreated with a function-blocking anti–PSGL-1 mAb PL1, ∼10% inhibition in lymphocyte binding to tonsil HEV was seen. When the anti–PSGL-1 mAb–treated PBL were added to anti–VAP-1 mAb–treated tonsil sections, 10% additive inhibitory effect on the adhesion was seen when compared to the effect of the anti– VAP-1 mAb alone. To assess the role of other sialomucins as potential counterreceptors for VAP-1, we treated lymphocytes with the sialomucin-degrading enzyme O-sialoglycoprotease, and then analyzed the VAP-1 dependence of their tonsil HEV binding. This treatment had a marginal effect on PBL adhesion to HEV, but the binding of O-sialoglycoprotease–treated cells was still efficiently blocked by mAb 1B2 pretreatment of the target tissue indicating that an O-sialoglycoprotease–sensitive molecule is not at least the principal lymphocyte ligand of VAP-1. Thus, none of the currently known lymphocyte adhesion molecules (L-selectin, α4 integrins, or PSGL-1) mediating rolling on endothelial cells are receptors for VAP-1.

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