Abstract
The efficacy of vaccination studies aimed at targeting antigens to human DC-SIGN (hDC-SIGN) have been notoriously difficult to study in vivo, as eight dendritic cell-specific intercellular adhesion molecule-3 grabbing non-integrin (DC-SIGN) homologs have been described in mice. CD209a/SIGNR5 has been coined as the mouse DC-SIGN (mDC-SIGN) ortholog, based on its expression and location in the genome. Nonetheless, which properties of hDC-SIGN are covered by mDC-SIGN is poorly investigated. One of the most important functions of DC-SIGN is the induction of adaptive immunity. As such, the aim of this study is to determine the capability of mDC-SIGN to induce adaptive immune responses. Here, we show that mDC-SIGN is expressed on GM-CSF cultured bone marrow-derived dendritic cells (BMDCs) and macrophages. However, mDC-SIGN is an internalizing receptor which, unlike hDC-SIGN, quickly resurfaces after internalization. Binding of OVA-coupled anti-mDC-SIGN antibody by BMDCs leads to quick internalization, processing, and presentation to antigen-specific CD8+ and CD4+ T cells, which can be boosted using the TLR4 ligand, monophosphoryl lipid A. In the homeostatic condition, mDC-SIGN is mostly expressed on myeloid cells in the skin and spleen. A subcutaneous injection of fluorescent anti-mDC-SIGN reveals specific targeting to mDC-SIGN+ skin dendritic cells (DCs) and monocyte-derived DCs in situ. A subcutaneous vaccination strategy containing OVA-coupled anti-mDC-SIGN antibody generated antigen-specific polyfunctional CD8+ T cell and CD4+ T cell responses and a strong isotype-switched OVA-specific antibody response in vivo. We conclude that mDC-SIGN shows partly overlapping similarities to hDC-SIGN and that targeting mDC-SIGN provides a valuable approach to investigate the immunological function of DC-SIGN in vivo.
Highlights
The human innate immune receptor dendritic cell-specific intercellular adhesion molecule-3 grabbing non-integrin (DC-SIGN) recognizes pathogen- and host-derived glycoproteins [1]
MDC-SIGN is higher expressed on GM-CSF cultured bone marrow-derived macrophages (GM-Macs) compared with GM-dendritic cells (DCs) cultured from bone marrow precursors
The C-type lectin receptor DC-SIGN has been described as a crucial innate immune receptor involved in a plethora of immunological processes, including the recognition of pathogen-derived ligands and self-glycoproteins, intracellular signaling, antigen processing and presentation, and activation of T cells [1]
Summary
The human innate immune receptor dendritic cell-specific intercellular adhesion molecule-3 grabbing non-integrin (DC-SIGN) recognizes pathogen- and host-derived glycoproteins [1]. It mediates antigen internalization, processing, and presentation of antigens to T cells, which are functional hallmarks of antigen-presenting cells (APCs). Subsequent targeting of antigens in this model has demonstrated the potency of hDC-SIGN on CD11c+ DCs to internalize, process, and present antigen to T cells [12, 13]. While it is evident that hDC-SIGN is an effective gateway to strong adaptive immunity, its expression on all CD11c+ cells limits its translational value as an in vivo model for antigen targeting
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