Production of type I interferons: plasmacytoid dendritic cells and beyond

Abstract

Plasmacytoid dendritic cells (pDCs) are specialized producers of type I interferons (IFNs) that respond to most viruses. Because of their antiviral activity and regulatory functions in innate and adaptive immunity, type I IFNs are important not only for antiviral resistance but also in other types of infections and in immune pathology. Here we discuss recent data that begin to reveal the unique molecular mechanisms underlying the remarkably rapid and efficient type I IFN production by pDCs.

Figure 1.

Human plasmacytoid DCs. Optical microscopy (A), transmission electron microscopy (B), and scanning electron microscopy (C) images showing the typical morphology of human pDCs. (D) Scanning electron microscopy image showing the dramatic morphological changes of activated pDCs after culture in the presence of IL-3 and CD40 ligand. All images are reproduced from Grouard et al. (3).

Figure 2.

Major signaling pathways for type I IFN gene transcription. TLR7 and TLR9 are highly expressed on pDCs and, depending on the chemical properties and formulation of the ligands used and on the cell type, activate signaling pathways involving either IRF-7 or IRF-5 and NF-κB. The IRF-7 pathway preferentially induces transcription of the type I IFN gene family and it is activated when the TLR–MyD88–IRAK–IRF-7 complex is retained in the endosomal compartment, as observed in pDCs treated with type A CpG ODNs. Other receptors able to induce production of type I IFN are TLR3 and TLR4 signaling through the adaptor molecule TRIF and the kinase TBK-1. TLR4, in addition to TRIF, also utilizes the adaptors TRAM, MyD88, and TIRAP (not shown in the figure). The cytoplasmic dsRNA receptor RIG-I also utilizes TBK-1. IRF-7 is required for optimal production of type I IFN induced by all these receptors, whereas IRF-3 is essential only for the response to TLR3 or TLR4. A positive feedback mechanism for IFN production involves the de novo synthesis of IRF-7 and IRF-8 in response to type I IFNs that amplify the transcription of all the genes of the type I IFN family.