Core 2 branching beta1,6-N-acetylglucosaminyltransferase and high endothelial venule-restricted sulfotransferase collaboratively control lymphocyte homing.
L-selectin mediates lymphocyte homing by facilitating lymphocyte adhesion to carbohydrate ligands expressed on high endothelial venules (HEV) of the secondary lymphoid organs. Previous studies demonstrated that L-selectin ligand sulfotransferase (LSST) forms 6-sulfo sialyl Lewis x (sLe(x)) on both core 2 branch and MECA-79-positive extended core 1 O-glycans, but the chemical nature and roles of HEV ligands elaborated by LSST and core 2 beta1,6-N-acetylglucosaminyltransferase-1 (Core2GlcNAcT) have been undefined. In the present study, we have generated mutant mice with deficient LSST and show that inactivation of LSST gene alone leads to only partial impairment of lymphocyte homing to peripheral lymph nodes and moderate reduction in lymphocyte counts in the peripheral lymph nodes, despite the fact that L-selectin ligands that contain 6-sulfo sLe(x) are reduced at HEV. By contrast, LSST/Core2GlcNAcT double null mice exhibited a markedly reduced lymphocyte homing and reduced lymphocyte counts as a result of significantly decreased 6-sulfo sLe(x) on HEV L-selectin counterreceptors, relative to LSST- or Core2GlcNAcT-single null mice. Moreover, induction of LSST and Core2GlcNAcT transcripts was observed in HEV-like structure formed in the salivary gland of the non-obese diabetic mouse, which displays chronic inflammation. These results indicate that LSST and Core2GlcNAcT cooperatively synthesize HEV-specific L-selectin ligands required for lymphocyte homing and suggest that LSST and Core2GlcNAcT play a critical role in lymphocyte trafficking during chronic inflammation.
Glycobiology Program, Cancer Research Center, The Burnham Institute, La Jolla, California 92037, USA.
Nobuyoshi
N
Hiraoka
Hiroto
H
Kawashima
Bronislawa
B
Petryniak
Jun
J
Nakayama
Junya
J
Mitoma
Jamey D
JD
Marth
John B
JB
Lowe
Minoru
M
Fukuda
D000818:Animals; D000954:Antigens, Surface / Q000378:metabolism; D002236:Carbohydrate Conformation; D002240:Carbohydrate Sequence; D002465:Cell Movement / Q000502:physiology*; D004729:Endothelium, Lymphatic / Q000166:cytology / Q000201:enzymology; D005260:Female; D008214:Lymphocytes / Q000166:cytology / Q000201:enzymology*; D008297:Male; D008565:Membrane Proteins; D051379:Mice; D008810:Mice, Inbred C57BL; D017351:N-Acetylglucosaminyltransferases / Q000502:physiology*; D009844:Oligosaccharides / Q000378:metabolism; D000080506:Sialyl Lewis X Antigen; D015238:Sulfotransferases / Q000737:chemistry / Q000502:physiology*
D000954:Antigens, Surface; C069886:L-selectin counter-receptors; D008565:Membrane Proteins; D009844:Oligosaccharides; D000080506:Sialyl Lewis X Antigen; D017351:N-Acetylglucosaminyltransferases; C053024:beta-1,3-galactosyl-O-glycosyl-glycoprotein beta-1,6-acetylglucosaminyl transferase; C120484:HEV-specific LSST; D015238:Sulfotransferases