The Journal of Experimental Medicine
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Published online 5 June 2006 doi:10.1084/jem.20052543
Rockefeller University Press, 0022-1007 $8.00
JEM, Volume 203, Number 6, 1603-1614
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ARTICLE

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

Eiji Umemoto1, Toshiyuki Tanaka1, Hidenobu Kanda1, Soojung Jin1, Kazuo Tohya3, Kazuhiro Otani1, Takahiro Matsutani1, Masanori Matsumoto1,2, Yukihiko Ebisuno1, Myoung Ho Jang1, Minoru Fukuda4, Takako Hirata2, and Masayuki Miyasaka1

1 Laboratory of Immunodynamics, Department of Microbiology and Immunology, Graduate School of Medicine and 2 The 21st Century Center of Excellence Program, Research Institute for Microbial Diseases, Osaka University, Osaka 565-0871, Japan
3 Department of Anatomy, Kansai College of Oriental Medicine, Osaka 590-0482, Japan
4 Glycobiology Program, Cancer Research Center, The Burnham Institute, La Jolla, CA 92037

CORRESPONDENCE Toshiyuki Tanaka: tanaka{at}orgctl.med.osaka-u.ac.jp

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.

Abbreviations used: C1GnT, core1 extension-ß1,3-N-acetylglucosaminyltransferase; C2GnT, core2 ß-1,6-N-acetylglucosaminyltransferase; FucTVII, {alpha}-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.


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