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Nepmucin, a novel HEV sialomucin, mediates L-selectin–dependent lymphocyte rolling and promotes lymphocyte adhesion under flow

Nepmucin, a novel HEV sialomucin, mediates L-selectin–dependent lymphocyte rolling and promotes... Lymphocyte trafficking to lymph nodes (LNs) is initiated by the interaction between lymphocyte L-selectin and certain sialomucins, collectively termed peripheral node addressin (PNAd), carrying specific carbohydrates expressed by LN high endothelial venules (HEVs). Here, we identified a novel HEV-associated sialomucin, nepmucin (mucin not expressed in Peyer's patches PPs), that is expressed in LN HEVs but not detectable in PP HEVs at the protein level. Unlike conventional sialomucins, nepmucin contains a single V-type immunoglobulin (Ig) domain and a mucin-like domain. Using materials affinity-purified from LN lysates with soluble L-selectin, we found that two higher molecular weight species of nepmucin (75 and 95 kD) were decorated with oligosaccharides that bind L-selectin as well as an HEV-specific MECA-79 monoclonal antibody. Electron microscopic analysis showed that nepmucin accumulates in the extended luminal microvillus processes of LN HEVs. Upon appropriate glycosylation, nepmucin supported lymphocyte rolling via its mucin-like domain under physiological flow conditions. Furthermore, unlike most other sialomucins, nepmucin bound lymphocytes via its Ig domain, apparently independently of lymphocyte function–associated antigen 1 and very late antigen 4, and promoted shear-resistant lymphocyte binding in combination with intercellular adhesion molecule 1. Collectively, these results suggest that nepmucin may serve as a dual-functioning PNAd in LN HEVs, mediating both lymphocyte rolling and binding via different functional domains. Footnotes Abbreviations used: C1GnT, core1 extension-β1,3- N -acetylglucosaminyltransferase; C2GnT, core2 β-1,6- N -acetylglucosaminyltransferase; FucTVII, α-1,3-fucosyltransferase VII; GlyCAM-1, glycosylation-dependent cell adhesion molecule 1; HEV, high endothelial venule; ICAM-1, intercellular adhesion molecule 1; LSST, L-selectin ligand sulfotransferase; MAdCAM-1, mucosal addressin cell adhesion molecule 1; OSGE, O -sialoglycoprotein endopeptidase; PNAd, peripheral node addressin; PP, Peyer's patch; VLA-4, very late antigen 4. Submitted: 22 December 2005 Accepted: 10 May 2006 http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png The Journal of Experimental Medicine Rockefeller University Press

Nepmucin, a novel HEV sialomucin, mediates L-selectin–dependent lymphocyte rolling and promotes lymphocyte adhesion under flow

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Publisher
Rockefeller University Press
Copyright
© 2006 Rockefeller University Press
ISSN
0022-1007
eISSN
1540-9538
DOI
10.1084/jem.20052543
pmid
16754720
Publisher site
See Article on Publisher Site

Abstract

Lymphocyte trafficking to lymph nodes (LNs) is initiated by the interaction between lymphocyte L-selectin and certain sialomucins, collectively termed peripheral node addressin (PNAd), carrying specific carbohydrates expressed by LN high endothelial venules (HEVs). Here, we identified a novel HEV-associated sialomucin, nepmucin (mucin not expressed in Peyer's patches PPs), that is expressed in LN HEVs but not detectable in PP HEVs at the protein level. Unlike conventional sialomucins, nepmucin contains a single V-type immunoglobulin (Ig) domain and a mucin-like domain. Using materials affinity-purified from LN lysates with soluble L-selectin, we found that two higher molecular weight species of nepmucin (75 and 95 kD) were decorated with oligosaccharides that bind L-selectin as well as an HEV-specific MECA-79 monoclonal antibody. Electron microscopic analysis showed that nepmucin accumulates in the extended luminal microvillus processes of LN HEVs. Upon appropriate glycosylation, nepmucin supported lymphocyte rolling via its mucin-like domain under physiological flow conditions. Furthermore, unlike most other sialomucins, nepmucin bound lymphocytes via its Ig domain, apparently independently of lymphocyte function–associated antigen 1 and very late antigen 4, and promoted shear-resistant lymphocyte binding in combination with intercellular adhesion molecule 1. Collectively, these results suggest that nepmucin may serve as a dual-functioning PNAd in LN HEVs, mediating both lymphocyte rolling and binding via different functional domains. Footnotes Abbreviations used: C1GnT, core1 extension-β1,3- N -acetylglucosaminyltransferase; C2GnT, core2 β-1,6- N -acetylglucosaminyltransferase; FucTVII, α-1,3-fucosyltransferase VII; GlyCAM-1, glycosylation-dependent cell adhesion molecule 1; HEV, high endothelial venule; ICAM-1, intercellular adhesion molecule 1; LSST, L-selectin ligand sulfotransferase; MAdCAM-1, mucosal addressin cell adhesion molecule 1; OSGE, O -sialoglycoprotein endopeptidase; PNAd, peripheral node addressin; PP, Peyer's patch; VLA-4, very late antigen 4. Submitted: 22 December 2005 Accepted: 10 May 2006

Journal

The Journal of Experimental Medicine – Rockefeller University Press

Published: Jun 12, 2006

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