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

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Abstract

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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Acknowledgements

We would like to thank the personnel of the Bergman clinic in Bilthoven, the Netherlands for providing healthy donor skin. We would like to thank Tom O’Toole for the technical assistance with imaging flow cytometry. The present work was funded by KWF (VU2009-2598), the Dutch Science Foundation (NWO, VENI Grant NO 863.10.017), the European Research Council (ERCAdvanced339977), and NanoNext 3D01.

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Authors and Affiliations

  1. Department of Molecular Cell Biology and Immunology,VU University Medical Center, Amsterdam, the Netherlands

    Cynthia M Fehres, Sanne Duinkerken, Sven CM Bruijns, Hakan Kalay, Sandra J van Vliet, Martino Ambrosini, Wendy WJ Unger, Juan J Garcia-Vallejo & Yvette van Kooyk

  2. Department of Medical Oncology, VU University Medical Center, Amsterdam, the Netherlands

    Tanja D de Gruijl

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  1. Cynthia M Fehres
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  2. Sanne Duinkerken
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Correspondence to Yvette van Kooyk.

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Fehres, C., Duinkerken, S., Bruijns, S. et al. Langerin-mediated internalization of a modified peptide routes antigens to early endosomes and enhances cross-presentation by human Langerhans cells. Cell Mol Immunol 14, 360–370 (2017). https://doi.org/10.1038/cmi.2015.87

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