Plasmacytoid dendritic cell biology and its role in immune-mediated diseases

Abstract

Plasmacytoid dendritic cells (pDCs) are a unique subset of dendritic cells specialised in secreting high levels of type I interferons. pDCs play a crucial role in antiviral immunity and have been implicated in the initiation and development of many autoimmune and inflammatory diseases. This review summarises the latest advances in recent years in several aspects of pDC biology, with special focus on pDC heterogeneity, pDC development via the lymphoid pathway, and newly identified proteins/pathways involved in pDC trafficking, nucleic acid sensing and interferon production. Finally, we also highlight the current understanding of pDC involvement in autoimmunity and alloreactivity, and opportunities for pDC-targeting therapies in these diseases. These new insights have contributed to answers to several fundamental questions remaining in pDC biology and may pave the way to successful pDC-targeting therapy in the future.

Keywords: alloreactivity; autoimmunity; cell development; immunotherapy; plasmacytoid dendritic cells.

Figure 1

Developmental pathways of pDCs. Major (heavy arrows) and minor (light arrows) haematopoietic pathways found to have the potential to produce plasmacytoid dendritic cells (pDCs) or conventional dendritic cells (cDC) are outlined. The progenitors include the following: HSS, haematopoietic stem cells; LMPP, lymphocyte primed multipotent precursors; CMP, common myeloid precursors; CLP, common lymphoid precursors; CDP, common dendritic precursors; LP, lymphoid precursors; pre‐cDC, precursors of cDC; and pre‐pDC, precursors of pDC. It is not yet clear whether a proportion of M‐CSFR^‐ CDP could be derived from LMPP via a more direct ‘bypass pathway’. CCR9⁻ pre‐pDC could differentiate into ‘cDC‐like’ cells context‐dependently, while these cells are not yet identified as real cDCs.

Figure 2

Routes of pDC sensing. Endosomal pathways: TLR7 senses RNA viruses and endogenous RNA, whereas TLR9 detects prokaryotes containing unmethylated CpG‐rich DNA sequences and endogenous DNA. Both TLR7 and TLR9 sense synthetic TLR ligands (CpG ODNs/imiquimod/R848) and immune complexes (self‐DNA/autoantibody and LL37/self‐DNA complexes mediated by FcγIIa). Non‐endosomal pathways: The cGAS (cyclic GMP‐AMP (cGAMP) synthase)–STING (stimulator of interferon genes) pathway senses cytosolic DNA and triggers an IRF3‐mediated IFN‐I production. Retinoic acid‐inducible gene I (RIG‐I) senses replicate viral RNA, recruits the mitochondrial antiviral signalling protein adaptor protein and leads to IFN‐I production. (DExD/H)‐box helicases DHX36 and DHX9 sense CpG ODNs, with the former selectively binding to CpG‐A and activating the IRF7 pathway and the latter selectively binding CpG‐B and activating the Nf‐ĸB pathway. pDCs sense polysaccharide A (PSA) via cytosolic TLR2 and activate the Nf‐ĸB pathway.