Sialyl-Lewis(x) on P-selectin glycoprotein ligand-1 is regulated during differentiation and maturation of dendritic cells: a mechanism involving the glycosyltransferases C2GnT1 and ST3Gal I.
To fulfil their function as APCs, dendritic cells (DC) and their precursors need to travel from blood to the peripheral tissues and, upon activation, migrate from tissues to draining lymph nodes. Because O-glycans play a role in T cell trafficking, we investigated the O-glycosylation profile of human monocyte-derived DC. Sialyl-Lewis(x) (sLe(x)), a glycan involved in extravasation via selectin binding, was found to be expressed exclusively on P-selectin glycoprotein ligand-1 in monocytes and immature DC. However, sLe(x) was lost from mature DC even though these cells retained expression of P-selectin glycoprotein ligand-1. Maturation of DC led to a rapid change in the expression of glycosyltransferases involved in O-linked glycosylation. A down-regulation of C2GnT1 mRNA and enzymatic activity was observed with a concurrent up-regulation of ST3Gal I and ST6GalNAc II mRNA resulting in a loss of the core 2 structures required for sLe(x) expression as a P-selectin ligand. Interestingly, the early regulation of these glycosyltransferases was mediated by PGE(2), which is known to be required for human DC migration. The pattern of O-glycosylation seen in mature cells was very similar to that expressed by naive T cells, which home to lymph nodes. Our data show that the regulation of O-glycosylation controls sLe(x) expression, and also suggest that O-glycans may have a function in DC migration.
Julien
Sylvain
S
Breast Cancer Biology Group, King's College London, Guy's Hospital, London, United Kingdom.
Grimshaw
Matthew J
MJ
Sutton-Smith
Mark
M
Coleman
Julia
J
Morris
Howard R
HR
Dell
Anne
A
Taylor-Papadimitriou
Joyce
J
Burchell
Joy M
JM
D002454:Cell Differentiation; D002465:Cell Movement; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000166:cytology* / Q000378:metabolism*; D015232:Dinoprostone / Q000494:pharmacology; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D016695:Glycosyltransferases / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007700:Kinetics; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000378:metabolism*; D009844:Oligosaccharides / Q000378:metabolism*; D011134:Polysaccharides / Q000096:biosynthesis; D012333:RNA, Messenger / Q000235:genetics; D054400:Receptors, CCR7 / Q000378:metabolism; D000080506:Sialyl Lewis X Antigen; D012799:Sialyltransferases / Q000378:metabolism*; D014158:Transcription, Genetic / Q000235:genetics; D000094663:beta-Galactoside alpha-2,3-Sialyltransferase
C515370:CCR7 protein, human; D008562:Membrane Glycoproteins; D009844:Oligosaccharides; C084882:P-selectin ligand protein; D011134:Polysaccharides; D012333:RNA, Messenger; D054400:Receptors, CCR7; D000080506:Sialyl Lewis X Antigen; D016695:Glycosyltransferases; D012799:Sialyltransferases; D020780:Matrix Metalloproteinase 9; D015232:Dinoprostone; D000094663:beta-Galactoside alpha-2,3-Sialyltransferase; C000722087:ST3GAL1 protein, human