Vascular Adhesion Protein 1 (VAP-1) Mediates Lymphocyte Subtype-specific, Selectin-independent Recognition of Vascular Endothelium in Human Lymph Nodes

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 α4 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.

Human Leukocyte Subpopulations from Inflamed Gut Bind to Joint Vasculature Using Distinct Sets of Adhesion Molecules

“…Note that the data for Table II was counted using darkfield microscopy of unstained cells, and hence the results (binding avidity of different cell types) can be readily compared with those obtained from frozen section assays in which unstained cells were used as well. vessels in lymph nodes, nor does it support synovial adherence of macrophages isolated from noninflamed gut (6,15). Hence, in the inflamed gut some nonphysiological stimuli involved in the synthesis of the as yet uncharacterized leukocyte ligand of VAP-1 apparently takes place, possibly on those macrophage subtypes that appear to be unique for IBD intestine (37).…”

“…Normally L-, E-, and P-selectins and their carbohydrate-containing mucin-like counterparts (like P-selectin glycoprotein ligand-1 (PSGL-1) for P-and E-selectin, and peripheral lymph node addressins (PNAd) for L-selectin) mediate the initial phases of extravasation (13). However, CD44 and vascular adhesion protein-1 (VAP-1) also contribute to the rolling of blood-borne cells (14,15). Chemokines are thought to be the key players in converting loosely rolling cells into stably bound cells (16).…”

CD73 Engagement Promotes Lymphocyte Binding to Endothelial Cells Via a Lymphocyte Function-Associated Antigen-1-Dependent Mechanism

“…An increase in the percentage of bound lymphocytes of all input lymphocytes subsequent to CD73 engagement in our binding experiments reflects the size of the CD73-positive cell population. To date, most studies concerning molecules involved in lymphocyte binding to endothelial cells have measured the binding of either unseparated lymphocytes or well-defined lymphocyte populations such as CD4-, CD8-, or CD19-positive cells, and of the studied molecules only the contribution of vascular adhesion protein-1 seems to be subtype restricted, i.e., it preferentially mediates adherence of CD8-positive cells to the endothelium (34). Our present results suggest that trafficking of lymphocytes in the body is not regulated only by the subtype-specific manner that is based on the conventional phenotype definition of the lymphocyte subpopulations.…”

Vascular Adhesion Protein 1 Mediates Binding of Immunotherapeutic Effector Cells to Tumor Endothelium

“…It is an endothelial adhesion molecule that is up-regulated at sites of inflammation and mediates lymphocyte binding to inflamed endothelium (6). VAP-1 is preferentially involved in adherence of CD8 ϩ (T killer) and CD16 ϩ (NK) lymphocytes to high endothelial venules (HEV) in peripheral lymph nodes and tonsils (7). Since TIL activated according to our protocol are predominantly CD8 ϩ (2,8), it would be possible that VAP-1 participates in homing of TIL.…”