Mouse DC-SIGN/CD209a as Target for Antigen Delivery and Adaptive Immunity

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.

Immunological dynamics after subcutaneous immunization with a squalene‐based oil‐in‐water adjuvant

“…45 This may explain the relative decrease in T cell frequency and stable B cell responses when moDCs are targeted at the peak of abundancy in the skin. We have corroborated previously results showing CD209a expression on cDC2s in the lymph node 23 which may explain the intact T cell responses using CD209a-targeting antibody (compared to untargeted approach) while increasing the humoral responses via moDCs. Finally, we have performed our functional immunization experiment including agonistic CD40 antibody (αCD40) as adjuvants accompanying the antigen (ie, vaccine).…”

Selective tumor antigen vaccine delivery to human CD169 + antigen-presenting cells using ganglioside-liposomes

“…This is crucial in the context of vaccine delivery and T cell activation for cancer immunotherapy. Indeed, we and others have previously shown that antigen targeting toward DC-SIGN using antibodies induces efficient antigen-specific T cell responses in in vitro and in vivo models (15,70,71). Using fucose-containing glycans as ligands to target DC-SIGN, we previously generated liposome or dendrimers to codeliver antigen and adjuvant to DC-SIGN + DCs.…”

Murine SIGNR1 (CD209b) Contributes to the Clearance of Uropathogenic Escherichia coli During Urinary Tract Infections

“…Further investigations are needed to determine the corresponding UPEC ligands, as we did previously for the identification of the carbohydrate LPS core from many Gram-negative bacteria (Klena et al, 2005;Zhang et al, 2006Zhang et al, , 2008Yang et al, 2015Yang et al, , 2019He et al, 2019;Ye et al, 2019). Several studies showed that in vivo targeting of CD209s drastically enhances antigen presentation as well as persistent CD8+/CD4+ T-cell-mediated protective immunity against intracellular pathogens (Singh et al, 2009;Unger et al, 2012;Hesse et al, 2013;Schetters et al, 2018). Thus, given the protective role of SIGNR1 in UTIs, the interaction between UPEC and CD209s should be targeted in treatment strategies to prevent persistent UTIs.…”