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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 mediates binding of both L-selectin–positive and –negative lymphocytes to PLN HEV. (A) Expression of L-selectin on different  lymphocyte populations. Total PBL, immunomagnetically separated L-selectin–positive and –negative subpopulations of PBL, and IL-2–activated T cells  were stained for L-selectin expression and analyzed using FACScan®. (B) L-selectin–negative T cells specifically recognize PLN HEVs. Five immunoblasts (black round cells, two pointed out by arrows) binding to a HEV (lilac basement membrane outlined by a dashed line) are shown in the micrograph. Bar, 20  μm. (C) Binding of these different lymphocytes to PLN HEVs after pretreatments with the indicated mAbs was analyzed.
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Figure 3: VAP-1 mediates binding of both L-selectin–positive and –negative lymphocytes to PLN HEV. (A) Expression of L-selectin on different lymphocyte populations. Total PBL, immunomagnetically separated L-selectin–positive and –negative subpopulations of PBL, and IL-2–activated T cells were stained for L-selectin expression and analyzed using FACScan®. (B) L-selectin–negative T cells specifically recognize PLN HEVs. Five immunoblasts (black round cells, two pointed out by arrows) binding to a HEV (lilac basement membrane outlined by a dashed line) are shown in the micrograph. Bar, 20 μm. (C) Binding of these different lymphocytes to PLN HEVs after pretreatments with the indicated mAbs was analyzed.

Mentions: To address these questions, we first used PLN-derived IL-2–dependent human immunoblasts that express no detectable surface L-selectin (Fig. 3 A, last column) and are LFA-1high, α4intermediate, β7intermediate, and CD44high. Intriguingly, these activated T cells bound 1.4 times better than PBL to PLN HEVs (Fig. 3 B and data not shown). As expected, no inhibition of binding was obtained by pretreating the immunoblasts with a function-blocking anti–L-selectin mAb Dreg-56 (Fig. 3 C). mAb MECA-79 pretreatment of PLNs also had essentially no effect on adhesion, confirming the absence of the L-selectin–PNAd pathway in this model. In contrast, mAb 1B2 pretreatment of target tissue abolished >50% of immunoblast binding (Fig. 3 C). Thus, L-selectin is not a prerequisite for adherence of all types of lymphoid cells to PLN HEVs under conditions of low shear, since cells can directly bind to 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 mediates binding of both L-selectin–positive and –negative lymphocytes to PLN HEV. (A) Expression of L-selectin on different  lymphocyte populations. Total PBL, immunomagnetically separated L-selectin–positive and –negative subpopulations of PBL, and IL-2–activated T cells  were stained for L-selectin expression and analyzed using FACScan®. (B) L-selectin–negative T cells specifically recognize PLN HEVs. Five immunoblasts (black round cells, two pointed out by arrows) binding to a HEV (lilac basement membrane outlined by a dashed line) are shown in the micrograph. Bar, 20  μm. (C) Binding of these different lymphocytes to PLN HEVs after pretreatments with the indicated mAbs was analyzed.
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Related In: Results  -  Collection

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Figure 3: VAP-1 mediates binding of both L-selectin–positive and –negative lymphocytes to PLN HEV. (A) Expression of L-selectin on different lymphocyte populations. Total PBL, immunomagnetically separated L-selectin–positive and –negative subpopulations of PBL, and IL-2–activated T cells were stained for L-selectin expression and analyzed using FACScan®. (B) L-selectin–negative T cells specifically recognize PLN HEVs. Five immunoblasts (black round cells, two pointed out by arrows) binding to a HEV (lilac basement membrane outlined by a dashed line) are shown in the micrograph. Bar, 20 μm. (C) Binding of these different lymphocytes to PLN HEVs after pretreatments with the indicated mAbs was analyzed.
Mentions: To address these questions, we first used PLN-derived IL-2–dependent human immunoblasts that express no detectable surface L-selectin (Fig. 3 A, last column) and are LFA-1high, α4intermediate, β7intermediate, and CD44high. Intriguingly, these activated T cells bound 1.4 times better than PBL to PLN HEVs (Fig. 3 B and data not shown). As expected, no inhibition of binding was obtained by pretreating the immunoblasts with a function-blocking anti–L-selectin mAb Dreg-56 (Fig. 3 C). mAb MECA-79 pretreatment of PLNs also had essentially no effect on adhesion, confirming the absence of the L-selectin–PNAd pathway in this model. In contrast, mAb 1B2 pretreatment of target tissue abolished >50% of immunoblast binding (Fig. 3 C). Thus, L-selectin is not a prerequisite for adherence of all types of lymphoid cells to PLN HEVs under conditions of low shear, since cells can directly bind to 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