Sulfation of L-selectin ligands by an HEV-restricted sulfotransferase regulates lymphocyte homing to lymph nodes.
Lymphocytes home to lymph nodes, using L-selectin to bind specific ligands on high endothelial venules (HEV). In vitro studies implicate GlcNAc-6-sulfate as an essential posttranslational modification for ligand activity. Here, we show that genetic deletion of HEC-GlcNAc6ST, a sulfotransferase that is highly restricted to HEV, results in the loss of the binding of recombinant L-selectin to the luminal aspect of HEV, elimination of lymphocyte binding in vitro, and markedly reduced in vivo homing. Reactivity with MECA 79, an adhesion-blocking mAb that stains HEV in lymph nodes and vessels in chronic inflammatory sites, is also lost from the luminal aspects of HEV. These results establish a critical role for HEC-GlcNAc6ST in lymphocyte trafficking and suggest it as an important therapeutic target.
Hemmerich
S
S
Department of Respiratory Diseases, Roche Bioscience, 3401 Hillview Avenue, Palo Alto, CA 94304, USA. sdr@itsa.ucsf.edu
Bistrup
A
A
Singer
M S
MS
van Zante
A
A
Lee
J K
JK
Tsay
D
D
Peters
M
M
Carminati
J L
JL
Brennan
T J
TJ
Carver-Moore
K
K
Leviten
M
M
Fuentes
M E
ME
Ruddle
N H
NH
Rosen
S D
SD
D000818:Animals; D002448:Cell Adhesion; D002634:Chemotaxis, Leukocyte; D019041:L-Selectin / Q000378:metabolism*; D037102:Lectins / Q000378:metabolism; D008024:Ligands; D008198:Lymph Nodes / Q000166:cytology*; D008208:Lymphatic System / Q000201:enzymology*; D008214:Lymphocytes / Q000166:cytology*; D051379:Mice; D008817:Mice, Mutant Strains; D015238:Sulfotransferases / Q000235:genetics / Q000378:metabolism*
D037102:Lectins; D008024:Ligands; D019041:L-Selectin; D015238:Sulfotransferases