title: Sialic acid-modified antigens impose tolerance via inhibition of T-cell proliferation and de novo induction of regulatory T cells.
abstract: Sialic acids are negatively charged nine-carbon carboxylated monosaccharides that often cap glycans on glycosylated proteins and lipids. Because of their strategic location at the cell surface, sialic acids contribute to interactions that are critical for immune homeostasis via interactions with sialic acid-binding Ig-type lectins (siglecs). In particular, these interactions may be of importance in cases where sialic acids may be overexpressed, such as on certain pathogens and tumors. We now demonstrate that modification of antigens with sialic acids (Sia-antigens) regulates the generation of antigen-specific regulatory T (Treg) cells via dendritic cells (DCs). Additionally, DCs that take up Sia-antigen prevent formation of effector CD4(+) and CD8(+)T cells. Importantly, the regulatory properties endowed on DCs upon Sia-antigen uptake are antigen-specific: only T cells responsive to the sialylated antigen become tolerized. In vivo, injection of Sia-antigen-loaded DCs increased de novo Treg-cell numbers and dampened effector T-cell expansion and IFN-γ production. The dual tolerogenic features that Sia-antigen imposed on DCs are Siglec-E-mediated and maintained under inflammatory conditions. Moreover, loading DCs with Sia-antigens not only inhibited the function of in vitro-established Th1 and Th17 effector T cells but also significantly dampened ex vivo myelin-reactive T cells, present in the circulation of mice with experimental autoimmune encephalomyelitis. These data indicate that sialic acid-modified antigens instruct DCs in an antigen-specific tolerogenic programming, enhancing Treg cells and reducing the generation and propagation of inflammatory T cells. Our data suggest that sialylation of antigens provides an attractive way to induce antigen-specific immune tolerance.
authors.affiliation: Department of Molecular Cell Biology and Immunology, VU University Medical Center, 1007 MB, Amsterdam, The Netherlands;
authors.forename: Maurizio
authors.initials: M
authors.lastname: Perdicchio
authors.affiliation: Department of Molecular Cell Biology and Immunology, VU University Medical Center, 1007 MB, Amsterdam, The Netherlands;
authors.forename: Juan M
authors.initials: JM
authors.lastname: Ilarregui
authors.affiliation: Department of Molecular Cell Biology and Immunology, VU University Medical Center, 1007 MB, Amsterdam, The Netherlands;
authors.forename: Marleen I
authors.initials: MI
authors.lastname: Verstege
authors.affiliation: Department of Molecular Cell Biology and Immunology, VU University Medical Center, 1007 MB, Amsterdam, The 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, 1007 MB, Amsterdam, The Netherlands;
authors.forename: Sjoerd T T
authors.initials: ST
authors.lastname: Schetters
authors.affiliation: Department of Molecular Cell Biology and Immunology, VU University Medical Center, 1007 MB, Amsterdam, The Netherlands;
authors.forename: Steef
authors.initials: S
authors.lastname: Engels
authors.affiliation: Department of Molecular Cell Biology and Immunology, VU University Medical Center, 1007 MB, Amsterdam, The Netherlands;
authors.forename: Martino
authors.initials: M
authors.lastname: Ambrosini
authors.affiliation: Department of Molecular Cell Biology and Immunology, VU University Medical Center, 1007 MB, Amsterdam, The Netherlands;
authors.forename: Hakan
authors.initials: H
authors.lastname: Kalay
authors.affiliation: Department of Molecular Cell Biology and Immunology, VU University Medical Center, 1007 MB, Amsterdam, The Netherlands;
authors.forename: Henrike
authors.initials: H
authors.lastname: Veninga
authors.affiliation: Department of Molecular Cell Biology and Immunology, VU University Medical Center, 1007 MB, Amsterdam, The Netherlands;
authors.forename: Joke M M
authors.initials: JM
authors.lastname: den Haan
authors.affiliation: Department of Pediatrics, Erasmus University Medical Center, 3000 CA, Rotterdam, The Netherlands;
authors.forename: Lisette A
authors.initials: LA
authors.lastname: van Berkel
authors.affiliation: Department of Pediatrics, Erasmus University Medical Center, 3000 CA, Rotterdam, The Netherlands;
authors.forename: Janneke N
authors.initials: JN
authors.lastname: Samsom
authors.affiliation: Division of Cell Signalling and Immunology, College of Life Sciences, University of Dundee, Dundee DD15 EH, United Kingdom;
authors.forename: Paul R
authors.initials: PR
authors.lastname: Crocker
authors.affiliation: Institute for Infection Immunology, TWINCORE, 30625 Hannover, Germany.
authors.forename: Tim
authors.initials: T
authors.lastname: Sparwasser
authors.affiliation: Institute for Infection Immunology, TWINCORE, 30625 Hannover, Germany.
authors.forename: Luciana
authors.initials: L
authors.lastname: Berod
authors.affiliation: Department of Molecular Cell Biology and Immunology, VU University Medical Center, 1007 MB, Amsterdam, The Netherlands;
authors.forename: Juan J
authors.initials: JJ
authors.lastname: Garcia-Vallejo
authors.affiliation: Department of Molecular Cell Biology and Immunology, VU University Medical Center, 1007 MB, Amsterdam, The Netherlands; y.vankooyk@vumc.nl.
authors.forename: Yvette
authors.initials: Y
authors.lastname: van Kooyk
authors.affiliation: Department of Molecular Cell Biology and Immunology, VU University Medical Center, 1007 MB, Amsterdam, The Netherlands;
authors.forename: Wendy W J
authors.initials: WW
authors.lastname: Unger
mesh_terms: D000222:Adaptation, Physiological / Q000276:immunology*; D000818:Animals; D000941:Antigens / Q000737:chemistry / Q000276:immunology*; D049109:Cell Proliferation; D051379:Mice; D008810:Mice, Inbred C57BL; D019158:N-Acetylneuraminic Acid / Q000737:chemistry*; D050378:T-Lymphocytes, Regulatory / Q000166:cytology / Q000276:immunology*
chemical_list: D000941:Antigens; D019158:N-Acetylneuraminic Acid
keywords: dendritic cells; glycans; regulatory T cells; sialic acids; tolerance