title: Interaction of polysialic acid with CCL21 regulates the migratory capacity of human dendritic cells.
abstract: Dendritic cells (DCs) are the most potent antigen-presenting cells (APCs). Immature DCs (iDCs) are situated in the periphery where they capture pathogen. Subsequently, they migrate as mature DCs (mDCs) to draining lymph nodes to activate T cells. CCR7 and CCL21 contribute to the migratory capacity of the DC, but it is not completely understood what molecular requirements are involved. Here we demonstrate that monocyte-derived DCs dramatically change ST8Sia IV expression during maturation, leading to the generation of polysialic acid (polySia). PolySia expression is highly upregulated after 2 days Toll-like receptor-4 (TLR4) triggering. Surprisingly, only immunogenic and not tolerogenic mDCs upregulated polySia expression. Furthermore, we show that polySia expression on DCs is required for CCL21-directed migration, whereby polySia directly captures CCL21. Corresponding to polySia, the expression level of CCR7 is maximal two days after TLR4 triggering. In contrast, although TLR agonists other than LPS induce upregulation of CCR7, they achieve only a moderate polySia expression. In situ we could detect polySia-expressing APCs in the T cell zone of the lymph node and in the deep dermis. Together our results indicate that prolonged TLR4 engagement is required for the generation of polySia-expressing DCs that facilitate CCL21 capture and subsequent CCL21-directed migration.
authors.affiliation: Department of Molecular Cell Biology and Immunology, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: Marieke
authors.initials: M
authors.lastname: Bax
authors.forename: Sandra J
authors.initials: SJ
authors.lastname: van Vliet
authors.forename: Manja
authors.initials: M
authors.lastname: Litjens
authors.forename: Juan J
authors.initials: JJ
authors.lastname: García-Vallejo
authors.forename: Yvette
authors.initials: Y
authors.lastname: van Kooyk
mesh_terms: D000938:Antigen-Presenting Cells / Q000166:cytology; D002465:Cell Movement; D054421:Chemokine CCL21 / Q000378:metabolism / Q000502:physiology*; D002633:Chemotaxis; D003713:Dendritic Cells / Q000166:cytology*; D005786:Gene Expression Regulation; D006801:Humans; D007150:Immunohistochemistry / Q000379:methods; D008198:Lymph Nodes / Q000378:metabolism / Q000473:pathology; D009000:Monocytes / Q000166:cytology; D009439:Neuraminidase / Q000378:metabolism; D011485:Protein Binding; D054400:Receptors, CCR7 / Q000378:metabolism; D012794:Sialic Acids / Q000378:metabolism*; D051197:Toll-Like Receptor 4 / Q000378:metabolism
chemical_list: C515478:CCL21 protein, human; C515370:CCR7 protein, human; D054421:Chemokine CCL21; D054400:Receptors, CCR7; D012794:Sialic Acids; C495345:TLR4 protein, human; D051197:Toll-Like Receptor 4; C021319:polysialic acid; D009439:Neuraminidase