The C-type lectin DC-SIGN internalizes soluble antigens and HIV-1 virions via a clathrin-dependent mechanism

Authors

  • Alessandra Cambi,

    1. Department of Tumor Immunology, Nijmegen Centre for Molecular Life Sciences, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands
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  • Inge Beeren,

    1. Department of Tumor Immunology, Nijmegen Centre for Molecular Life Sciences, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands
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  • Ben Joosten,

    1. Department of Tumor Immunology, Nijmegen Centre for Molecular Life Sciences, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands
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  • Jack A. Fransen,

    1. Microscopic Imaging Centre, Nijmegen Centre for Molecular Life Sciences, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands
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  • Carl G. Figdor

    Corresponding author
    1. Department of Tumor Immunology, Nijmegen Centre for Molecular Life Sciences, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands
    • Department of Tumor Immunology, Nijmegen Centre for Molecular Life Sciences, Radboud University, Nijmegen Medical Centre, Postbox 9101, 6500 HB Nijmegen, The Netherlands Fax: +31-24-3540339

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Abstract

Dendritic cells (DC), professional Ag-presenting cells located in mucosae and lymphoid organs, operate at the interface of innate and adaptive immunity and are likely the first cells to encounter invading HIV-1. Although the C-type lectin DC-Specific ICAM-3-grabbing non-integrin (DC-SIGN) binds to several viruses, including HIV-1, its direct involvement in viral entry remains controversial. Despite its central role in DC function, little is known about the underlying molecular mechanism(s) of DC-SIGN-mediated Ag uptake. Here, we analyzed the early stages of DC-SIGN-mediated endocytosis and demonstrate that both membrane cholesterol and dynamin are required. Confocal microscopy and clathrin RNAi showed that DC-SIGN-mediated internalization occurs via clathrin-coated pits. Electron microscopy of ultrathin sections showed the involvement of DC-SIGN in clathrin-dependent HIV-1 internalization by DC. Currently, DC-specific C-type lectins are considered potential target in anti-tumor clinical trials. Detailed information about how different Ag are internalized via these receptors will facilitate the rational design of targeted therapeutic strategies.

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