title: Allergy-Protective Arabinogalactan Modulates Human Dendritic Cells via C-Type Lectins and Inhibition of NF-κB.
abstract: Arabinogalactan (AG) isolated from dust of a traditional farm prevents disease in murine models of allergy. However, it is unclear whether this polysaccharide has immune regulatory properties in humans. The aim of this study was to test the influence of AG on the immune-stimulating properties of human dendritic cells (DCs). Moreover, we sought to identify the receptor to which AG binds. AG was produced from plant callus tissue under sterile conditions to avoid the influence of pathogen-associated molecular patterns in subsequent experiments. The influence of AG on the human immune system was investigated by analyzing its impact on monocyte-derived DCs. To analyze whether the T cell stimulatory capacity of AG-stimulated DCs is altered, an MLR with naive Th cells was performed. We revealed that AG reduced T cell proliferation in a human MLR. In the search for a molecular mechanism, we found that AG binds to the immune modulatory receptors DC-specific ICAM-3 -: grabbing non integrin (DC-SIGN) and macrophage mannose receptor 1 (MMR-1). Stimulation of these receptors with AG simultaneously with TLR4 stimulation with LPS increased the expression of the E3 ubiquitin-protein ligase tripartite motif -: containing protein 21 and decreased the phosphorylation of NF-κB p65 in DCs. This led to a reduced activation profile with reduced costimulatory molecules and proinflammatory cytokine production. Blocking of MMR-1 or DC-SIGN with neutralizing Abs partially inhibits this effect. We conclude that AG dampens the activation of human DCs by LPS via binding to DC-SIGN and MMR-1, leading to attenuated TLR signaling. This results in a reduced T cell activation capacity of DCs.
authors.affiliation: Department of Experimental Pneumology, Ruhr University Bochum, 44801 Bochum, Germany; marcus.peters@rub.de.
authors.forename: Marcus
authors.identifier: http://orcid.org/0000-0003-1850-2845
authors.initials: M
authors.lastname: Peters
authors.affiliation: Department of Experimental Pneumology, Ruhr University Bochum, 44801 Bochum, Germany;
authors.forename: Patrick M
authors.identifier: http://orcid.org/0000-0003-4737-2293
authors.initials: PM
authors.lastname: Guidato
authors.affiliation: Department of Experimental Pneumology, Ruhr University Bochum, 44801 Bochum, Germany;
authors.forename: Karin
authors.initials: K
authors.lastname: Peters
authors.affiliation: Medical Proteome Center, Ruhr University Bochum, 44801 Bochum, Germany; and.
authors.forename: Dominik A
authors.identifier: http://orcid.org/0000-0002-1058-7744
authors.initials: DA
authors.lastname: Megger
authors.affiliation: Medical Proteome Center, Ruhr University Bochum, 44801 Bochum, Germany; and.
authors.forename: Barbara
authors.initials: B
authors.lastname: Sitek
authors.affiliation: Department of Pharmaceutical Biology, Christian Albrechts University, 24118 Kiel, Germany.
authors.forename: Birgit
authors.identifier: http://orcid.org/0000-0003-1452-801X
authors.initials: B
authors.lastname: Classen
authors.affiliation: Department of Pharmaceutical Biology, Christian Albrechts University, 24118 Kiel, Germany.
authors.forename: Esther M
authors.initials: EM
authors.lastname: Heise
authors.affiliation: Department of Experimental Pneumology, Ruhr University Bochum, 44801 Bochum, Germany;
authors.forename: Albrecht
authors.initials: A
authors.lastname: Bufe
mesh_terms: D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D003713:Dendritic Cells / Q000187:drug effects / Q000276:immunology*; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D005685:Galactans / Q000276:immunology* / Q000494:pharmacology; D006801:Humans; D006967:Hypersensitivity / Q000276:immunology; D037181:Lectins, C-Type / Q000276:immunology*; D008213:Lymphocyte Activation / Q000187:drug effects / Q000276:immunology*; D007959:Lymphocyte Culture Test, Mixed; D016328:NF-kappa B / Q000276:immunology*; D015398:Signal Transduction / Q000276:immunology
chemical_list: D005685:Galactans; D037181:Lectins, C-Type; D016328:NF-kappa B; C005653:arabinogalactan