1. Design of neo-glycoconjugates that target the mannose receptor and enhance TLR-independent cross-presentation and Th1 polarization.
- Author
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Singh SK, Streng-Ouwehand I, Litjens M, Kalay H, Burgdorf S, Saeland E, Kurts C, Unger WW, and van Kooyk Y
- Subjects
- Animals, CD8-Positive T-Lymphocytes cytology, CD8-Positive T-Lymphocytes immunology, Cell Proliferation, Cells, Cultured, Endosomes immunology, Lectins, C-Type deficiency, Lewis Blood Group Antigens, Mannose Receptor, Mannose-Binding Lectins deficiency, Mice, Mice, Inbred C57BL, Receptors, Cell Surface deficiency, Th1 Cells cytology, Toll-Like Receptors immunology, Cell Polarity, Cross-Priming, Glycoconjugates immunology, Lectins, C-Type immunology, Mannose-Binding Lectins immunology, Oligosaccharides immunology, Receptors, Cell Surface immunology, Th1 Cells immunology, Trisaccharides immunology
- 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., (Copyright © 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)
- Published
- 2011
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