title: Glycan modification of antigen alters its intracellular routing in dendritic cells, promoting priming of T cells.
abstract: Antigen uptake by dendritic cells and intracellular routing of antigens to specific compartments is regulated by C-type lectin receptors that recognize glycan structures. We show that the modification of Ovalbumin (OVA) with the glycan-structure Lewis(X) (Le(X)) re-directs OVA to the C-type lectin receptor MGL1. Le(X)-modification of OVA favored Th1 skewing of CD4(+) T cells and enhanced cross-priming of CD8(+) T cells. While cross-presentation of native OVA requires high antigen dose and TLR stimuli, Le(X) modification reduces the required amount 100-fold and obviates its dependence on TLR signaling. The OVA-Le(X)-induced enhancement of T cell cross-priming is MGL1-dependent as shown by reduced CD8(+) effector T cell frequencies in MGL1-deficient mice. Moreover, MGL1-mediated cross-presentation of OVA-Le(X) neither required TAP-transporters nor Cathepsin-S and was still observed after prolonged intracellular storage of antigen in Rab11(+)LAMP1(+) compartments. We conclude that controlled neo-glycosylation of antigens can crucially influence intracellular routing of antigens, the nature and strength of immune responses and should be considered for optimizing current vaccination strategies.
authors.affiliation: Department of Molecular Cell Biology and Immunology, VU University Medical Center, Amsterdam, Netherlands.
authors.forename: Ingeborg
authors.initials: I
authors.lastname: Streng-Ouwehand
authors.affiliation: Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, Leiden, Netherlands.
authors.forename: Nataschja I
authors.initials: NI
authors.lastname: Ho
authors.affiliation: Department of Molecular Cell Biology and Immunology, VU University Medical Center, Amsterdam, Netherlands.
authors.forename: Manja
authors.initials: M
authors.lastname: Litjens
authors.affiliation: Department of Molecular Cell Biology and Immunology, VU University Medical Center, Amsterdam, Netherlands.
authors.forename: Hakan
authors.initials: H
authors.lastname: Kalay
authors.affiliation: Department of Molecular Cell Biology and Immunology, VU University Medical Center, Amsterdam, Netherlands.
authors.forename: Martine Annemarie
authors.initials: MA
authors.lastname: Boks
authors.affiliation: Department of Molecular Cell Biology and Immunology, VU University Medical Center, Amsterdam, Netherlands.
authors.forename: Lenneke A M
authors.initials: LA
authors.lastname: Cornelissen
authors.affiliation: Department of Molecular Cell Biology and Immunology, VU University Medical Center, Amsterdam, Netherlands.
authors.forename: Satwinder
authors.initials: S
authors.lastname: Kaur Singh
authors.affiliation: Department of Molecular Cell Biology and Immunology, VU University Medical Center, Amsterdam, Netherlands.
authors.forename: Eirikur
authors.initials: E
authors.lastname: Saeland
authors.affiliation: Department of Molecular Cell Biology and Immunology, VU University Medical Center, Amsterdam, Netherlands.
authors.forename: Juan J
authors.initials: JJ
authors.lastname: Garcia-Vallejo
authors.affiliation: Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, Leiden, Netherlands.
authors.forename: Ferry A
authors.initials: FA
authors.lastname: Ossendorp
authors.affiliation: Department of Molecular Cell Biology and Immunology, VU University Medical Center, Amsterdam, Netherlands.
authors.forename: Wendy W J
authors.initials: WW
authors.lastname: Unger
authors.affiliation: Department of Molecular Cell Biology and Immunology, VU University Medical Center, Amsterdam, Netherlands.
authors.forename: Yvette
authors.identifier: http://orcid.org/0000-0001-5997-3665
authors.initials: Y
authors.lastname: van Kooyk
mesh_terms: D000818:Animals; D000941:Antigens / Q000737:chemistry* / Q000378:metabolism*; D001212:Asialoglycoproteins / Q000172:deficiency / Q000378:metabolism; D003713:Dendritic Cells / Q000378:metabolism*; D037181:Lectins, C-Type / Q000172:deficiency / Q000378:metabolism; D008565:Membrane Proteins / Q000172:deficiency / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D010047:Ovalbumin / Q000737:chemistry* / Q000378:metabolism*; D011134:Polysaccharides / Q000378:metabolism*; D021381:Protein Transport; D013601:T-Lymphocytes / Q000276:immunology*
chemical_list: D000941:Antigens; D001212:Asialoglycoproteins; C064720:Clec10a protein, mouse; D037181:Lectins, C-Type; D008565:Membrane Proteins; D011134:Polysaccharides; D010047:Ovalbumin
keywords: MGL1; T cell priming; cross-presentation; dendritic cells; glycosylation; immunology; mouse