Design of neo‐glycoconjugates that target the mannose receptor and enhance TLR‐independent cross‐presentation and Th1 polarization
Open Access
- 17 January 2011
- journal article
- antigen processing
- Published by Wiley in European Journal of Immunology
- Vol. 41 (4), 916-925
- https://doi.org/10.1002/eji.201040762
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-LewisA 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-LewisA 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-LewisA 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.Keywords
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