Distinct dendritic cell (DC) subsets express different patterns of Toll-like receptors (TLRs), and this has been proposed to determine the type of immune response that is induced by microorganisms. However, a recent study published in The Journal of Experimental Medicine now indicates that both plasmacytoid DCs (pDCs) and conventional DCs (cDCs) are activated in vivo by ligands for TLR4, TLR7 and TLR9 but that the type of response and its dependence on type I interferons (IFNs) differs between the two DC subsets.

In this study, Asselin-Paturel et al. set out to investigate which DC subset produces type I IFNs — cytokines (such as IFN-α and IFN-β) that have an important role in the antiviral immune response and that have been suggested to promote DC maturation — after in vivo stimulation with TLR ligands. As expected, administration of a TLR7 or TLR9 ligand (resiquimod or CpG-containing oligodeoxynucleotides (ODNs), respectively), but not a TLR4 ligand (lipopolysaccharide, LPS), to wild-type mice induced production of type I IFNs by pDCs but not by cDCs. The production of type I IFNs in response to CpG ODNs, but not resiquimod, was dependent on expression of the type I IFN receptor (IFNAR), indicating that in vivo production of type I IFNs in response to distinct TLR ligands is differentially regulated.

In contrast to type I IFN production, LPS, resiquimod and CpG ODNs each induced in vivo upregulation of CD40 and CD86 expression by pDCs and cDCs. In vivo activation of pDCs by each of these ligands was dependent on IFNAR expression; however, only resiquimod- and CpG-ODN-mediated activation of cDCs was IFNAR dependent. By contrast, CpG ODNs and resiquimod, but not LPS, induced IFNAR-dependent migration of pDCs to the marginal zone of the spleen and the outer T-cell area, where they formed clusters, whereas all three ligands induced the migration of cDCs to the T-cell area of the spleen, in an IFNAR-independent manner. Further analysis indicated that pDCs from mice treated with CpG ODNs showed reduced chemotaxis towards the CXC-chemokine receptor 3 (CXCR3) ligand CXC-chemokine ligand 9 (CXCL9) and increased chemotaxis towards the CC-chemokine receptor 7 (CCR7) ligands CC-chemokine ligand 19 (CCL19) and CCL21. Interestingly, in vivo induction of CXCL9 and CXCL10 expression in response to CpG ODNs was IFNAR dependent, leading the authors to suggest that this could partly explain the dependence of CpG-ODN-mediated pDC migration on type I IFNs.