CpG oligonucleotides locating to early or late endosomes induce innate or adaptive immune responses, respectively, in PDCs.

Guiducci et al. report on page 1999 that plasmacytoid dendritic cells (PDCs) mount either innate or adaptive immune responses depending on the subcellular localization of foreign DNA.

PDCs are very rare in the body (making up less than 1% of the cells in the blood) but are important for antiviral immune responses. Activation of the endosomal receptor TLR9 by viral DNA can induce PDCs either to mount an innate response (marked by their ability to produce IFN-α) or to mature into antigen-presenting adaptive immune cells. How these two fates are determined was unclear.

The two fates can also be induced using three different classes of synthetic oligonucleotides called CpG immunostimulatory sequences. CpG-A normally induces IFN-α production, CpG-B induces maturation, and CpG-C can induce both. Now, Guiducci et al. show that the location of the oligonucleotides appears to determine PDC response: an early endosome location leads to an innate response, and a late endosome location leads to an adaptive response.

Oligonucleotide location could be manipulated based on oligonucleotide structure. The group found that multimerizing CpG-B switched its location from late to early endosomes and switched its effect from maturation to the induction of IFN-α production. The opposite transformation was possible with the normally multimeric CpG-A: reducing it to a monomer shifted it from early to late endosomes and altered the effect from IFN-α production to maturation.

CpG-C was found in both early and late endosomes, as might be expected based on its dual effect on PDCs. By preventing its interaction with TLR9 in early endosomes, the team found that CpG-C could no longer induce IFN-α production, but its ability to induce maturation remained intact.

Multiple questions remain. It is unclear why the spatial structure of the oligonucleotides would determine location or why location would determine the type of immune response. The larger mystery is why PDCs are using such a mechanism to regulate the nature of their immune response to viruses.

What we do know is that many viruses locate to early and/or late endosomes. The authors suggest that PDCs have adapted to this behavior of viruses and are able to mount the appropriate immune response for the stage of infection or the type of virus. This, says senior author Franck Barrat, makes them “the perfect weapon against viruses.”