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Plasmacytoid dendritic cells: sensing nucleic acids in viral infection and autoimmune diseases

Nature Reviews Immunology volume 8, pages 594–606 (2008)Cite this article

Key Points

  • The mammalian innate immune system seems to have developed three distinct systems to sense viral infection through the recognition of nucleic acids. These are the endosomal Toll-like receptor 7 (TLR7)/TLR8/TLR9 signalling pathway through MyD88 (myeloid differentiation primary-response gene 88), the endosomal TLR3 signalling pathway through TRIF (Toll/interleukin-1 (IL-1) receptor-domain-containing adaptor protein inducing interferon-β) and the cytosolic RIG-I (retinoic-acid-inducible gene I) signalling pathway.

  • The endosomal TLR7/TLR9–MyD88 pathway is exclusively used by plasmacytoid dendritic cells (pDCs). pDCs use neither the endosomal TLR8–MyD88 pathway nor the TLR3–TRIF pathway, which are instead mainly used by myeloid cells, such as myeloid DCs, to detect viral RNA. In addition, pDCs do not use the cytosolic RIG-I pathway, which is widely used by myeloid cells and all non-haematopoietic cells to detect viral double-stranded RNA.

  • pDCs seem to detect A-type CpG-containing DNA in the early endosomes through TLR9 that is coupled to interferon-regulatory factor 7 (IRF7) activation and leads to type I interferon (IFN) production. By contrast, pDCs sense B-type CpG-containing DNA in the late endosomes through TLR9 that is coupled to nuclear factor-κB (NF-κB) activation and leads to tumour-necrosis factor and IL-6 production, as well as to the maturation of the pDCs into mature antigen-presenting cells.

  • Several host factors, including DNA-specific antibodies, the antimicrobial peptide LL37, the nuclear DNA-binding protein HMGB1 (high-mobility group box 1 protein) or small ribonucleoprotein, allow self DNA or self RNA to activate both autoreactive B cells and pDCs through endosomal TLR9 or TLR7, leading to the development of autoimmune diseases, such as systemic lupus erythematosus and psoriasis.

  • pDCs may detect self DNA and self RNA frequently and mount low level of type I IFN responses when cell death occurs in normal tissues during tissue renewal, stress and repair processes.

  • This unwanted pDC response is potentially under tight control by rapid clearance of dying cells by macrophages; by degradation of self DNA and self RNA by DNases and RNases, respectively; by compartmentalization of TLR7 and TLR9 within the endosomes; and by receptor-mediated negative regulation of TLR7- or TLR9-induced IFN responses in pDCs.

Abstract

Plasmacytoid dendritic cells (pDCs) are important mediators of antiviral immunity through their ability to produce large amounts of type I interferons (IFNs) on viral infection. This function of pDCs is linked to their expression of Toll-like receptor 7 (TLR7) and TLR9, which sense viral nucleic acids within the early endosomes. Exclusion of self nucleic acids from TLR-containing early endosomes normally prevents pDC responses to them. However, in some autoimmune diseases, self nucleic acids can be modified by host factors and gain entrance to pDC endosomes, where they activate TLR signalling. Several pDC receptors negatively regulate type I IFN responses by pDCs during viral infection and for normal homeostasis.

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Figure 1: Overview of the human TLR family.
Figure 2: Intracellular nucleic-acid sensors and signalling pathways.
Figure 3: Activation pathway in plasmacytoid dendritic cells responding to nucleic acids.
Figure 4: Signalling of CpG ODN classes in different endosomal compartments.
Figure 5: A model for sensing self DNA.
Figure 6: Dendritic-cell regulatory receptors and the ITAM pathway in the regulation of TLR responses.

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Acknowledgements

We thank the former and current members of the laboratory for their critical contributions, the M.D. Anderson Cancer Foundation and The Dana Foundation for financial support, M. Haject for editorial assistance, T. Kim, M. Bao and K. Arima for critical reading of the manuscript. This Review is dedicated to Dr Ralph Steinman for his support and encouragement.

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  1. Michel Gilliet and Wei Cao: These authors contributed equally to this manuscript.

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  1. Department of Immunology and Center of Cancer Immunology Research, The University of Texas M. D. Anderson Cancer Center, Houston, 77030, Texas, USA

    Michel Gilliet, Wei Cao & Yong-Jun Liu

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Glossary

Type I interferons

Molecules produced by cells of the immune system that are rapidly induced by infection with viruses and bacteria. They immediately limit viral replication and increase subsequent antigen-specific immune responses.

CpG-containing DNA

DNA oligodeoxynucleotide sequences that include a cytidine–guanosine sequence and certain flanking nucleotides. These sequences have been found to induce innate immune responses through interaction with Toll-like receptor 9.

Pattern-recognition receptors

Host receptors that can sense pathogen-associated molecular patterns and initiate signalling cascades that lead to an innate immune response. These can be membrane bound (for example, Toll-like receptors) or soluble cytoplasmic receptors (for example, RIG-I, MDA5 and NLRs).

A-type CpG ODNs

(Also known as D-type CpG ODNs). Synthetic oligodeoxynucleotides (ODNs) with the following three features: polyG sequences at the 3′ end; a central palindromic sequence; and cytosine-guanine dinucleotides within the palindrome. The polyG tails on A-type CpG ODNs can interact with each other, resulting in the formation of guanine tetrads and clusters.

B-type CpG ODNs

(Also known as K-type CpG ODNs). Synthetic oligodeoxynucleotides that contain a CpG motif(s) on a phosphorothioate backbone.

Pathogen-associated molecular patterns

(PAMPs). Molecular patterns that are found in pathogens but not mammalian cells. Examples include terminally mannosylated and polymannosylated compounds (which bind the mannose receptor) and various microbial components, such as bacterial lipopolysaccharide, hypomethylated DNA, flagellin and double-stranded RNA (all of which bind Toll-like receptors).

Death domain

A protein–protein interaction domain found in many proteins that are involved in signalling and apoptosis.

DExD/H box RNA helicases

A group of enzymes that can unwind double-stranded RNA using energy derived from ATP hydrolysis. The DExD/H box is a characteristic amino-acid signature motif of many RNA-binding proteins.

Caspase-recruitment domain

(CARD). A protein domain that is found in certain initiator caspases (for example, mammalian caspase-9) and their adaptor proteins (for example, apoptotic-protease-activating factor 1, APAF1). This domain mediates protein–protein interactions.

Inflammasome

A molecular complex of several proteins that, on assembly, cleaves pro-interleukin-1, thereby producing active interleukin-1.

Ubiquitin E3 ligase

An enzyme that is required to attach the molecular tag ubiquitin to proteins. Depending on the position and number of ubiquitin molecules that are attached, the ubiquitin tag can target proteins for degradation in the proteasomal complex, sort them to specific subcellular compartments or modify their biological activity.

Osteopontin

An extracellular matrix protein that supports adhesion and migration of inflammatory cells. It has recently been recognized as an immunoregulatory T-helper-1-type cytokine.

Systemic lupus erythematosus

(SLE). An autoimmune disease in which autoantibodies specific for DNA, RNA or proteins associated with nucleic acids form immune complexes that damage small blood vessels, especially in the kidneys. Patients with SLE generally have abnormal B- and T-cell function.

CpG islands

Sequences of 0.5–2 kilobases that are rich in CpG dinucleotides. They are mostly located upstream of housekeeping genes and are also present in some tissue-specific genes. They are constitutively non-methylated in all animal cell types.

Immune complexes

Complexes of antigen bound to antibody and, sometimes, components of the complement system. The levels of immune complexes are increased in many autoimmune disorders, in which they become deposited in tissues and cause tissue damage.

Immunoreceptor-based tyrosine activation motif

(ITAM). A structural motif containing tyrosine residues, found in the cytoplasmic tails of several signalling molecules. The motif has the form Tyr-Xaa-Xaa-Leu/Ile, and the tyrosine is a target for phosphorylation by SRC tyrosine kinases and subsequent binding of proteins containing SRC-homology-2 domains.

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Gilliet, M., Cao, W. & Liu, YJ. Plasmacytoid dendritic cells: sensing nucleic acids in viral infection and autoimmune diseases. Nat Rev Immunol 8, 594–606 (2008). https://doi.org/10.1038/nri2358

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