Distinguishing Self from Foreign DNA

Abstract

Toll-like receptors (TLRs) recognize conserved motifs associated with pathogens, which allows them to differentiate "self" from "nonself" and to initiate immune responses. Whereas TLRs that recognize bacterial and fungal structures are found in the plasma membrane, TLRs that recognize bacterial and viral nucleic acids are located inside of cells (see Bauer). Barton et al. investigated the functional importance of the intracellular localization of TLR9, a TLR that is activated by DNA containing unmethylated CpG motifs, which occur frequently in bacterial and viral DNA. Immunofluorescence analysis of chimeric receptors containing the extracellular domain of CD4 and transmembrane or cytosolic domains of TLR9 or TLR4 (which localizes to the plasma membrane) revealed that localization depended on the TLR transmembrane domain. TLR9N4C, a chimeric receptor that contained the TLR9 ectodomain and the TLR4 cytosolic and transmembrane domains, localized to the cell surface. When expressed in HEK293T cells and stimulated with CpG oligonucleotides (CpG DNA), TLR9N4C activated an NF-κB-luciferase reporter as effectively as TLR9; furthermore, the response of TLR9N4C to CpG DNA, unlike that of TLR9, was insensitive to pharmacological blockade of endosomal acidification. Similarly, dendritic cells expressing TLR9N4C responded to CpG DNA as effectively as cells expressing TLR9 did. However, dendritic cells expressing TLR9N4C, unlike those expressing TLR9, failed to respond to herpes simplex virus 2 (HSV-2). Moreover, macrophages expressing TLR9N4C, but not macrophages expressing TLR9, were stimulated by exposure to extracellular mammalian DNA. Thus, the authors propose that the intracellular localization of TLR9 may be critical to its ability to discriminate self from viral nucleic acids. G. M. Barton, J. C. Kagan, R. Medzhitov, Intracellular localization of Toll-like receptor 9 prevents recognition of self DNA but facilitates access to viral DNA. Nat. Immunol . 7 , 49-56 (2006). [PubMed] S. Bauer, Toll-erating self DNA. Nat. Immunol . 7 , 13-15 (2006). [PubMed]