Systematic Dual Targeting of Dendritic Cell C-Type Lectin Receptor DC-SIGN and TLR7 Using a Trifunctional Mannosylated Antigen
| Autor: | Michel Thépaut, Franck Fieschi, Corinne Vivès, Sandra J. van Vliet, Hans van den Elst, Tim Arnoldus, Sven C. M. Bruijns, Rui Jun Eveline Li, Nico J. Meeuwenoord, Gijs A. van der Marel, Herman S. Overkleeft, Tim P Hogervorst, Dmitri V. Filippov, Jeroen D. C. Codée, Silvia Achilli, Yvette van Kooyk, Chung C. Wong |
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| Přispěvatelé: | Molecular cell biology and Immunology, AGEM - Digestive immunity, AGEM - Re-generation and cancer of the digestive system, CCA - Cancer biology and immunology, AII - Cancer immunology, Department of Molecular Cell Biology and Immunology (Academic Medical Center, Amsterdam), VU University Medical Center [Amsterdam], Department of Bio-organic Synthesis, Faculty of Science, Leiden Institute of Chemistry, Institut de biologie structurale (IBS - UMR 5075 ), Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS), Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA) |
| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
Antigen presentation
02 engineering and technology 010402 general chemistry 01 natural sciences DC-SIGN lcsh:Chemistry Antigen C-type lectin mannoside vaccine model tumor-associated antigens Original Research TLR7 biology [SDV.BBM.BS]Life Sciences [q-bio]/Biochemistry Molecular Biology/Structural Biology [q-bio.BM] Chemistry Pattern recognition receptor General Chemistry Dendritic cell 021001 nanoscience & nanotechnology Ligand (biochemistry) Acquired immune system 0104 chemical sciences 3. Good health Cell biology lcsh:QD1-999 glyco-antigen biology.protein 0210 nano-technology peptide conjugate |
| Zdroj: | Frontiers in Chemistry, 7:650. Bentham Science Publishers B.V. Frontiers in Chemistry Frontiers in Chemistry, Vol 7 (2019) Frontiers in chemistry, 7, 650 Li, R J E, Hogervorst, T P, Achilli, S, Bruijns, S C, Arnoldus, T, Vivès, C, Wong, C C, Thépaut, M, Meeuwenoord, N J, van den Elst, H, Overkleeft, H S, van der Marel, G A, Filippov, D V, van Vliet, S J, Fieschi, F, Codée, J D C & van Kooyk, Y 2019, ' Systematic Dual Targeting of Dendritic Cell C-Type Lectin Receptor DC-SIGN and TLR7 Using a Trifunctional Mannosylated Antigen ', Frontiers in Chemistry, vol. 7, 650 . https://doi.org/10.3389/fchem.2019.00650 Frontiers in Chemistry, Frontiers Media, 2019, 7, pp.650. ⟨10.3389/fchem.2019.00650⟩ Frontiers in chemistry Frontiers in Chemistry, 2019, 7, pp.650. ⟨10.3389/fchem.2019.00650⟩ |
| ISSN: | 1567-2042 2296-2646 |
| DOI: | 10.3389/fchem.2019.00650 |
| Popis: | International audience; Dendritic cells (DCs) are important initiators of adaptive immunity, and they possess a multitude of Pattern Recognition Receptors (PRR) to generate an adequate T cell mediated immunity against invading pathogens. PRR ligands are frequently conjugated to tumor-associated antigens in a vaccination strategy to enhance the immune response toward such antigens. One of these PPRs, DC-SIGN, a member of the C-type lectin receptor (CLR) family, has been extensively targeted with Lewis structures and mannose glycans, often presented in multivalent fashion. We synthesized a library of well-defined mannosides (mono-, di-, and tri-mannosides), based on known "high mannose" structures, that we presented in a systematically increasing number of copies (n = 1, 2, 3, or 6), allowing us to simultaneously study the effect of mannoside configuration and multivalency on DC-SIGN binding via Surface Plasmon Resonance (SPR) and flow cytometry. Hexavalent presentation of the clusters showed the highest binding affinity, with the hexa-α1,2-di-mannoside being the most potent ligand. The four highest binding hexavalent mannoside structures were conjugated to a model melanoma gp100-peptide antigen and further equipped with a Toll-like receptor 7 (TLR7)-agonist as adjuvant for DC maturation, creating a trifunctional vaccine conjugate. Interestingly, DC-SIGN affinity of the mannoside clusters did not directly correlate with antigen presentation enhancing properties and the α1,2-di-mannoside cluster with the highest binding affinity in our library even hampered T cell activation. Overall, this systematic study has demonstrated that multivalent glycan presentation can improve DC-SIGN binding but enhanced binding cannot be directly translated into enhanced antigen presentation and the sole assessment of binding affinity is thus insufficient to determine further functional biological activity. Furthermore, we show that well-defined antigen conjugates combining two different PRR ligands can be generated in a modular fashion to increase the effectiveness of vaccine constructs. |
| Databáze: | OpenAIRE |
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