title: Design of neo-glycoconjugates that target the mannose receptor and enhance TLR-independent cross-presentation and Th1 polarization.
abstract: Cross-presentation is an important mechanism by which DCs present exogenous antigens on MHC-I molecules, and activate CD8(+) T cells, cells that are crucial for the elimination of tumors. We investigated the feasibility of exploiting the capacity of the mannose receptor (MR) to improve both cross-presentation of tumor antigens and Th polarization, processes that are pivotal for the anti-tumor potency of cytotoxic T cells. To this end, we selected two glycan ligands of the MR, 3-sulfo-Lewis(A) and tri-GlcNAc (N-acetylglucosamine), to conjugate to the model antigen OVA and assessed in vitro the effect on antigen presentation and Th differentiation. Our results demonstrate that conjugation of either 3-sulfo-Lewis(A) or tri-GlcNAc specifically directs antigen to the MR. Both neo-glycoconjugates showed, even at low doses, improved uptake as compared with native OVA, resulting in enhanced cross-presentation. Using MR(-/-) and MyD88-TRIFF(-/-) bone marrow-derived DCs (BMDCs), we show that the cross-presentation of the neo-glycoconjugates is dependent on MR and independent of TLR-mediated signaling. Whereas proliferation of antigen-specific CD4(+) T cells was unchanged, stimulation with neo-glycoconjugate-loaded DCs enhanced the generation of IFN-γ-producing T cells. We conclude that modification of antigen with either 3-sulfo-Lewis(A) or tri-GlcNAc enhances cross-presentation and permits Th1 skewing, through specific targeting of the MR, which may be beneficial for DC-based vaccination strategies to treat cancer.
authors.affiliation: Department of Molecular Cell Biology and Immunology, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: Satwinder Kaur
authors.initials: SK
authors.lastname: Singh
authors.forename: Ingeborg
authors.initials: I
authors.lastname: Streng-Ouwehand
authors.forename: Manja
authors.initials: M
authors.lastname: Litjens
authors.forename: Hakan
authors.initials: H
authors.lastname: Kalay
authors.forename: Sven
authors.initials: S
authors.lastname: Burgdorf
authors.forename: Eirikur
authors.initials: E
authors.lastname: Saeland
authors.forename: Christian
authors.initials: C
authors.lastname: Kurts
authors.forename: Wendy W
authors.initials: WW
authors.lastname: Unger
authors.forename: Yvette
authors.initials: Y
authors.lastname: van Kooyk
mesh_terms: D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology; D016764:Cell Polarity; D049109:Cell Proliferation; D002478:Cells, Cultured; D045142:Cross-Priming; D011992:Endosomes / Q000276:immunology; D006001:Glycoconjugates / Q000276:immunology*; D037181:Lectins, C-Type / Q000172:deficiency / Q000276:immunology*; D007983:Lewis Blood Group Antigens; D000090323:Mannose Receptor; D037241:Mannose-Binding Lectins / Q000172:deficiency / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D009844:Oligosaccharides / Q000276:immunology*; D011956:Receptors, Cell Surface / Q000172:deficiency / Q000276:immunology*; D018417:Th1 Cells / Q000166:cytology / Q000276:immunology*; D051193:Toll-Like Receptors / Q000276:immunology; D014312:Trisaccharides / Q000276:immunology*
chemical_list: D006001:Glycoconjugates; D037181:Lectins, C-Type; D007983:Lewis Blood Group Antigens; D000090323:Mannose Receptor; D037241:Mannose-Binding Lectins; D009844:Oligosaccharides; D011956:Receptors, Cell Surface; D051193:Toll-Like Receptors; D014312:Trisaccharides; C116504:sulfo-Lewis(a); C019117:N,N',N''-triacetylchitotriose