Plasmacytoid dendritic cells in antiviral immunity and autoimmunity

Abstract

Plasmacytoid dendritic cells (pDCs) represent a unique and crucial immune cell population capable of producing large amounts of type I interferons (IFNs) in response to viral infection. The function of pDCs as the professional type I IFN-producing cells is linked to their selective expression of Toll-like receptor 7 (TLR7) and TLR9, which sense viral nucleic acids within the endosomal compartments. Type I IFNs produced by pDCs not only directly inhibit viral replication but also play an essential role in linking the innate and adaptive immune system. The aberrant activation of pDCs by self nucleic acids through TLR signaling and the ongoing production of type I IFNs do occur in some autoimmune diseases. Therefore, pDC may serve as an attractive target for therapeutic manipulations of the immune system to treat viral infectious diseases and autoimmune diseases.

Figure 1

Morphology of pDCs. A–C, Giemsa staining of pDCs (A), monocytes (B) and CD11c⁺ mDCs (C); D, transmission EM of pDCs; E, scanning EM of immature pDCs; F, scanning EM of mature pDCs activated by IL-3 and CD40L. Original magnifications, 1000×(A,B,C), 7000×(D) and 3000×(E,F).

Figure 2

The activation pathway of pDCs responding to viral nucleic acids and negative regulation of the pDC function by surface receptors. When exposed to viruses or nucleic acids, TLR7 and TLR9 translocate to the endosome to get engaged with ssRNA or dsDNA, leading to the conformational changes in the TLRs. Then a multi-protein signaling complex is formed, including MyD88, BTK, TRAF6, IRAK1, and IRAK4, and this complex activates MAPKs and transcriptional factors, such as NF-κB, and IRF7. Following the activation, the transcription factors translocate into nuclei and initiate the transcription of type I IFNs, pro-inflammatory cytokines (such as IL-6 and TNF-α), and co-stimulatory molecules (such as CD80, CD86). Meanwhile, pDCs express some surface regulatory receptors, such as BDCA-2, ILT7, NKp44, and Siglec-H, to inhibit type I IFNs production through the ITAM signaling pathway.

Figure 3

A model for recognition of self-DNA and self-RNA by pDCs. LL37 binds self-DNA and self-RNA fragments released by dying cells to form aggregated and condensed structures that are protected from extracellular nuclease degradation. HMGB1, derived from the dying cells, binds aggregated self-DNA-LL37 complexes or dsDNA-autoantibodies immune complexes and promotes their association with TLR9 through interacting with RAGE. In SLE, the aberrantly expressed IFN-α from pDCs, together with IL-6, stimulates the differentiation of autoreactive B cells into plasma cells and expression of B cell survival factor BAFF. This could contribute to amplification of the pathogenic loop in which pDCs produce more type I IFNs and subsequently promote the differentiation of autoreactive plasma cells that would further secret autoantibodies to form immune complexes to activate pDCs.