The idea of dendritic-cell (DC) plasticity is gaining momentum, but the ability to secrete large quantities of the type 1 interferons (IFNs), IFN-α and IFN-β, in response to infection with viruses has long been considered a special feature of plasmacytoid DCs. These cytokines are important for linking innate and adaptive immune responses. But now, Diebold and colleagues report a further level of DC plasticity — other types of DC can also produce large quantities of type 1 IFNs.

Because some studies indicated that plasmacytoid DCs are not essential for the production of type I IFNs following infection with the Armstrong strain of lymphocytic choriomeningitis virus (LCMV), Diebold and colleagues decided to investigate which other cell types can produce type 1 IFNs. Non-plasmacytoid CD11chi DCs isolated from mice that were infected with the DC-tropic Armstrong variant clone 13 could produce large quantities of type I IFNs after in vitro culture.

The authors next investigated the link between virus infection and the production of type I IFNs. They used the synthetic double-stranded RNA (dsRNA) mimic polyI:C to stimulate non-plasmacytoid DCs. Mimicking virus infection by cytosolic delivery (by electroporation or delivery with lipofectamine) of polyI:C or virus dsRNA to splenic DCs or bone-marrow-derived DCs enabled them to produce as much type I IFN as plasmacytoid DCs. This was found to be independent of signals delivered through the receptor for dsRNA, Toll-like receptor 3 (TLR3), as the production of IFN-α by bone-marrow-derived DCs from TLR3-deficient mice was unimpaired. Mice deficient in the TLR-adaptor MyD88 could also produce IFN-α, indicating that production of IFN-α by these DCs is TLR independent.

So, if the TLR pathway isn't important, how is dsRNA recognized by non-plasmcytoid DCs? Protein kinase R (PKR) can bind dsRNA and has been implicated in IFN responses to virus infection. Using PKR-deficient DCs or inhibiting PKR activity led to a reduction in the level of type 1 IFNs, but an increase in the level of interleukin-12, in response to stimulation with polyI:C plus lipofectamine and CD40 ligand.

Many viruses can evade PKR-mediated responses — for example, influenza virus encodes the NS1 protein, which can bind and sequester dsRNA. Does this allow the virus to block the production of type I IFNs by non-plasmacytoid DCs? Non-plasmacytoid bone-marrow-derived DCs produce low levels of IFN-α when infected with influenza virus, but infection with an NS1-deficient virus variant resulted in the production of high levels of IFN-α, even though this variant infects only a small fraction of bone-marrow-derived DCs. Interestingly, influenza virus is often used to stimulate the production of type I IFNs by plasmacytoid DCs.

These results show that non-plasmacytoid DCs can produce large amounts of type I IFNs during infection with virus and, once again, studying viruses has indicated something new about the immune system — a TLR-independent pathway for the activation of DCs.