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Schistosomiasis is a major helminthic disease in which damage to the affected organs is orchestrated by a pathogenic host CD4 T helper (Th) cell-mediated immune response against parasite eggs. In the case of the species Schistosoma mansoni , the resulting granulomatous inflammation and fibrosis takes place in the liver and intestines. The magnitude of disease varies greatly from individual to individual but in a minority of patients, there is severe disease and death. S. mansoni infection in a murine model similarly results in marked strain variation of immunopathology. In the most commonly examined mouse strain, C57BL/6 (BL/6), there is relatively mild hepatic pathology arising in a Th2-dominated cytokine environment. In contrast, CBA mice develop decisively more severe lesions largely driven by proinflammatory IL-17-producing Th17 cells. Dendritic cells (DCs) from CBA mice differ sharply with those from BL/6 mice in that they vastly over-express the C-type lectin receptor (CLR) CD209a (SIGNR5), a homolog of human DC-SIGN, which senses glycans such as those produced by schistosome eggs. Silencing of CD209a, and recent studies with CD209a KO CBA mice have shown that this receptor is crucial to induce the pathogenic Th17 cell response; indeed, CD209a KO mice display markedly reduced immunopathology akin to that seen in BL/6 mice. Mechanistically, CD209a synergizes with the related CLRs Dectin-2 and Mincle to stimulate increased DC production of IL-1β and IL-23, necessary for pathogenic Th17 cell development. These findings denote key molecular underpinnings of disease variability based on selection and function of contrasting Th cell subsets.

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 .