Abstract
Microbial DNA is highly immunostimulatory and is sensed by endosomal pattern recognition receptors after release from internalized microbes. It is unclear how extracellular DNA released from dead microbes is delivered to endosomal PRRs to induce immune responses. Here we have investigated the ability of DCs to bind and internalize extracellular E.coli DNA as well as synthetic DNA. DCs internalized E.coli and synthetic DNA, which was dependent on the C-type lectin receptor DC-SIGN. Notably, endosomal uptake of DNA by DCs enhanced TLR9-dependent responses of B cells against DNA. Hence, we have identified DC-SIGN as a cell surface receptor for DNA that facilitates immune responses directed against DNA.
Highlights
Dendritic cells (DCs) are key players in sensing invading microbes and subsequent initiation of pathogen-specific adaptive immune responses
Microbial DNA is a potent inducer of immune responses and TLR9-mediated recognition of microbial DNA is pivotal for effective immunity against pathogenic microbes [27,28,29]
It is unclear how TLR9-mediated responses against extracellular microbial DNA are facilitated by cell surface receptors
Summary
Dendritic cells (DCs) are key players in sensing invading microbes and subsequent initiation of pathogen-specific adaptive immune responses. DCs sense conserved pathogen-associated molecular patterns (PAMPs) of microbes via pattern recognition receptors (PRRs), which induce innate signaling to activate DCs. DCs express numerous PRRs, including Toll-like receptors (TLRs) and C-type lectin receptors (CLRs) [1,2]. TLRs are either expressed as cellsurface receptors or as endosomal receptors and TLR localization is crucial for their activation and specificity [3,4]. TLR9 resides in endosomes and is activated by nonmethylated cytosineguanine (CpG) motifs, which are twenty times more abundant in microbial DNA compared to mammalian DNA [5]. Microbial DNA is only accessible to TLR9 after degradation of microbes in endolysosomal compartments, which adds to the specificity of TLR9 and prevents activation by CpG motifs within self DNA as self DNA is normally not present in endolysosomal vesicles [6]
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