Cross-presentation through langerin and DC-SIGN targeting requires different formulations of glycan-modified antigens

Fehres, Cynthia M.; Kalay, Hakan; Bruijns, Sven C. M.; Musaafir, Sara A.M.; Ambrosini, Martino; Bloois, Louis van; Vliet, Sandra J. van; Storm, Gerrit; García-Vallejo, Juan J.; Kooyk, Yvette van

doi:10.1016/j.jconrel.2015.01.040

Cited by 67 publications

(86 citation statements)

References 48 publications

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“…Previous ex vivo studies have explored the use of natural glycans such as Le Y for this purpose 29 .…”

Section: Discussionmentioning

confidence: 99%

“…Liposomes represent versatile nanoparticles that have been approved for the delivery of chemotherapeutics in Kaposi's sarcoma and allow for the co-formulation of adjuvants 27,28 . They can be targeted to glycan-binding proteins (GBPs) including CLRs or sialic acidbinding immunoglobulin-like lectins (Siglecs) expressed on immune cells using glycans or glycomimetic ligands [29][30][31] .…”

Section: Introductionmentioning

confidence: 99%

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A specific, glycomimetic Langerin ligand for human Langerhans cell targeting

Wamhoff

Bellmann

Bachem

et al. 2018

Preprint

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Langerhans cells are a subset of dendritic cells residing in the epidermis of the human skin. As such, they are key mediators of immune regulation and have emerged as prime targets for novel transcutaneous cancer vaccines. Importantly, the induction of protective T cell immunity by these vaccines requires the efficient and specific delivery of both tumor-associated antigens and adjuvants.Langerhans cells uniquely express Langerin (CD207), an endocytic C-type lectin receptor. Here, we report the discovery of a specific, glycomimetic Langerin ligand employing a heparin-inspired design strategy that integrated NMR spectroscopy and molecular docking. The conjugation of these glycomimetics to liposomes enabled the specific and efficient targeting of Langerhans cells in the human skin. This delivery platform provides superior versatility and scalability over antibody-based approaches and thus addresses current limitations of dendritic cell-based immunotherapies.

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“…Previous ex vivo studies have explored the use of natural glycans such as Le Y for this purpose 29 .…”

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

A specific, glycomimetic Langerin ligand for human Langerhans cell targeting

Wamhoff

Bellmann

Bachem

et al. 2018

Preprint

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“…9 We have recently demonstrated that differences in the size of the antigen influence langerin-mediated antigen internalization and cross-presentation in LCs. 47 Bigger nanoparticles are less well internalized and cross-presented by LCs compared to small, soluble peptides. 29 These findings might explain the discrepancy found between the Van der Vlist study and the data presented here.…”

Section: Discussionmentioning

confidence: 99%

Langerin-mediated internalization of a modified peptide routes antigens to early endosomes and enhances cross-presentation by human Langerhans cells

et al. 2015

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The potential of the skin immune system to generate immune responses is well established, and the skin is actively exploited as a vaccination site. Human skin contains several antigen-presenting cell subsets with specialized functions. In particular, the capacity to cross-present exogenous antigens to CD8+ T cells is of interest for the design of effective immunotherapies against viruses or cancer. Here, we show that primary human Langerhans cells (LCs) were able to cross-present a synthetic long peptide (SLP) to CD8 T cells. In addition, modification of this SLP using antibodies against the receptor langerin, but not dectin-1, further enhanced the cross-presenting capacity of LCs through routing of internalized antigens to less proteolytic early endosome antigen 1 early endosomes. The potency of LCs to enhance CD8 T-cell responses could be further increased through activation of LCs with the toll-like receptor 3 ligand polyinosinic:polycytidylic acid (pI:C). Altogether, the data provide evidence that human LCs are able to cross-present antigens after langerin-mediated internalization. Furthermore, the potential for antigen modification to target LCs specifically provides a rationale for generating effective anti-tumor or anti-viral cytotoxic T lymphocyte responses.

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“…The interaction of DC-SIGN with pathogens, triggers specific signaling events that modulate DC activity at various levels, influencing phagocytosis16, suppressing TLR-induced maturation of DCs15, internalizing pathogen-derived molecules12, modifying DC-adhesion and migration17 and antigen presentation181920, and regulating T-cell activation by DCs47. In addition, DC-SIGN has also been involved in the induction of anti-inflammatory signals that result in the induction of anergic T cells21.…”

mentioning

confidence: 99%

Fasciola hepatica glycoconjugates immuneregulate dendritic cells through the Dendritic Cell-Specific Intercellular adhesion molecule-3-Grabbing Non-integrin inducing T cell anergy

Rodríguez

Kalay

Noya

et al. 2017

Sci Rep

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Dendritic cell-specific ICAM-3 grabbing non-integrin (DC-SIGN) expressed on a variety of DCs, is a C-type lectin receptor that recognizes glycans on a diverse range of pathogens, including parasites. The interaction of DC-SIGN with pathogens triggers specific signaling events that modulate DC-maturation and activity and regulate T-cell activation by DCs. In this work we evaluate whether F. hepatica glycans can immune modulate DCs via DC-SIGN. We demonstrate that DC-SIGN interacts with F. hepatica glycoconjugates through mannose and fucose residues. We also show that mannose is present in high-mannose structures, hybrid and trimannosyl N-glycans with terminal GlcNAc. Furthermore, we demonstrate that F. hepatica glycans induce DC-SIGN triggering leading to a strong production of TLR-induced IL-10 and IL-27p28. In addition, parasite glycans induced regulatory DCs via DC-SIGN that decrease allogeneic T cell proliferation, via the induction of anergic/regulatory T cells, highlighting the role of DC-SIGN in the regulation of innate and adaptive immune responses by F. hepatica. Our data confirm the immunomodulatory properties of DC-SIGN triggered by pathogen-derived glycans and contribute to the identification of immunomodulatory glyans of helminths that might eventually be useful for the design of vaccines against fasciolosis.

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Cross-presentation through langerin and DC-SIGN targeting requires different formulations of glycan-modified antigens

Cited by 67 publications

References 48 publications

A specific, glycomimetic Langerin ligand for human Langerhans cell targeting

A specific, glycomimetic Langerin ligand for human Langerhans cell targeting

Langerin-mediated internalization of a modified peptide routes antigens to early endosomes and enhances cross-presentation by human Langerhans cells

Fasciola hepatica glycoconjugates immuneregulate dendritic cells through the Dendritic Cell-Specific Intercellular adhesion molecule-3-Grabbing Non-integrin inducing T cell anergy

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