Plasmacytoid Dendritic Cells: Recent Progress and Open Questions

Reizis, Boris; Bunin, Anna; Ghosh, Hiyaa S.; Lewis, Kanako L.; Sisirak, Vanja

doi:10.1146/annurev-immunol-031210-101345

Cited by 529 publications

(526 citation statements)

References 151 publications

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“…In this regard, it has been shown that commensal microbiota provide an important source of PRR ligands under steady state that are important to facilitate antiviral immunity [32][33][34]. While we can exclude this route of paracrine priming in our in vitro assays, this mode of action might be of relevance for optimal pDC responses in vivo.The natural capacity of pDCs to produce high amounts of type I IFN has been ascribed to the constitutive expression of IRF7 in pDCs [35]. It has been proposed that this endogenous IRF7 expression is critical for IFNAR-independent rapid interferon production.…”

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confidence: 99%

Self‐priming determines high type I IFN production by plasmacytoid dendritic cells

et al. 2014

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Plasmacytoid dendritic cells (pDCs) are responsible for the robust and immediate production of type I IFNs during viral infection. pDCs employ TLR7 and TLR9 to detect RNA and CpG motifs present in microbial genomes. CpG-A was the first synthetic stimulus available that induced large amounts of IFN-α (type I IFN) in pDCs. CpG-B, however, only weakly activates pDCs to produce IFN-α. Here, we demonstrate that differences in the kinetics of TLR9 activation in human pDCs are essential for the understanding of the functional difference between CpG-A and CpG-B. While CpG-B quickly induces IFN-α production in pDCs, CpG-A stimulation results in delayed yet maximal IFN-α induction. Constitutive production of low levels of type I IFN in pDCs, acting in a paracrine and autocrine fashion, turned out to be the key mechanism responsible for this phenomenon. At high cell density, pDC-derived, constitutive type I IFN production primes pDCs for maximal TLR responsiveness. This accounts for the high activity of higher structured TLR agonists that trigger type I IFN production in a delayed fashion. Altogether, these data demonstrate that high type I IFN production by pDCs cannot be simply ascribed to cell-autonomous mechanisms, yet critically depends on the local immune context. Keywords:CpG-A r CpG-B r pDC r TLR9 r Type I IFN Additional supporting information may be found in the online version of this article at the publisher's web-site IntroductionThe recognition of invading pathogens and the initiation of an appropriate immune response are key functions of the innate immune system. TLRs are a family of PRRs that sense conserved microbial signatures, also known as PAMPs [1,2]. Among these, TLR9 detects unmethylated CpG-motifs, which are present in viral Correspondence: Prof. Veit Hornung e-mail: veit.hornung@uni-bonn.de and bacterial DNA, whereas TLR7 senses uridine-rich RNA. To prevent recognition of endogenous nucleic acids, both TLR7 and TLR9 are confined to endosomal compartments that are usually devoid of nucleic acids. While both TLR7 and TLR9 are broadly expressed in innate immune cells of the murine system, both TLR7 and TLR9 show a far more restricted expression pattern within the human system, with TLR9 expression restricted to B cells and pDCs. * These authors equally contributed to this work.C 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim www.eji-journal.eu 808Sarah Kim et al. Eur. J. Immunol. 2014. 44: 807-818 TLR9 traffics from the endoplasmic reticulum through the Golgi apparatus to acidic endosomal compartments, where it is proteolytically cleaved to achieve its signaling-competent state. Following ligand engagement, TLR9 initiates a signaling cascade, which is dependent on MyD88. In pDCs, MyD88 triggers a signaling complex consisting of IRAK1/4, TRAF3, and IKKα that leads to phosphorylation and nuclear translocation of interferon regulatory factor 7 (IRF7) and transcription of type I IFN genes. At the same time, TLR9 engagement activates NF-κB and subsequent proinflammatory gene expression [3]. For TLR9, di...

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Self‐priming determines high type I IFN production by plasmacytoid dendritic cells

et al. 2014

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“…This occurs mainly through a rapid type I IFN (IFN-α/β) production 7, 31, 32 . Selective depletion of PDC by genetic approaches supports the critical role of PDC for early IFN-α production after microbial infections 33– 35 .…”

Section: The Innate Immune Functions Of Plasmacytoid Dendritic Cellsmentioning

confidence: 99%

Recent insights into the implications of metabolism in plasmacytoid dendritic cell innate functions: Potential ways to control these functions

Saas¹,

Varin²,

Perruche³

et al. 2017

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There are more and more data concerning the role of cellular metabolism in innate immune cells, such as macrophages or conventional dendritic cells. However, few data are available currently concerning plasmacytoid dendritic cells (PDC), another type of innate immune cells. These cells are the main type I interferon (IFN) producing cells, but they also secrete other pro-inflammatory cytokines (e.g., tumor necrosis factor or interleukin [IL]-6) or immunomodulatory factors (e.g., IL-10 or transforming growth factor-β). Through these functions, PDC participate in antimicrobial responses or maintenance of immune tolerance, and have been implicated in the pathophysiology of several autoimmune diseases. Recent data support the idea that the glycolytic pathway (or glycolysis), as well as lipid metabolism (including both cholesterol and fatty acid metabolism) may impact some innate immune functions of PDC or may be involved in these functions after Toll-like receptor (TLR) 7/9 triggering. Some differences may be related to the origin of PDC (human versus mouse PDC or blood-sorted versus FLT3 ligand stimulated-bone marrow-sorted PDC). The kinetics of glycolysis may differ between human and murine PDC. In mouse PDC, metabolism changes promoted by TLR7/9 activation may depend on an autocrine/paracrine loop, implicating type I IFN and its receptor IFNAR, explaining a delayed glycolysis. Moreover, PDC functions can be modulated by the metabolism of cholesterol and fatty acids. This may occur via the production of lipid ligands that activate nuclear receptors (e.g., liver X receptor [LXR]) in PDC or through limiting intracellular cholesterol pool size (by statins or LXR agonists) in these cells. Finally, lipid-activated nuclear receptors ( i.e., LXR or peroxisome proliferator activated receptor) may also directly interact with pro-inflammatory transcription factors, such as NF-κB. Here, we discuss how glycolysis and lipid metabolism may modulate PDC functions and how this may be harnessed in pathological situations where PDC play a detrimental role.

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“…18 pDCs present a spherical shape that resembles plasma cells and produce high amounts of type I interferons following Toll-like receptor 7 (TLR7) or TLR9 activation. 3,19 pDCs are not phagocytic and are considered inefficient inducers of CD4 þ T-cell responses. Similarly to cDCs, pDCs are also derived from bone marrow progenitors in an Flt3L-dependent manner.…”

Section: Classes Of Dcsmentioning

confidence: 99%

Role and therapeutic value of dendritic cells in central nervous system autoimmunity

2014

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Dendritic cells (DCs) are professional antigen-presenting cells that control the generation of adaptive immunity. Consequently, DCs have a central role in the induction of protective immunity to pathogens and also in the pathogenic immune response responsible for the development and progression of autoimmune disorders. Thus the study of the molecular pathways that control DC development and function is likely to result in new strategies for the therapeutic manipulation of the immune response. In this review, we discuss the role and therapeutic value of DCs in autoimmune diseases, with a special focus on multiple sclerosis. Cell Death and Differentiation (2015) 22, 215-224; doi:10.1038/cdd.2014; published online 29 August 2014 FactsDendritic cells (DCs) control central and peripheral tolerance through their effects on effector and regulatory T cells. Specific signaling pathways regulate the ability of different DC populations to promote effector and regulatory T-cell responses. Abnormalities in DC numbers, recruitment and function contribute to the pathology of multiple sclerosis (MS) and can be partially overcome by the use of disease-modifying therapies and the targeting of specific molecular pathways. Nanotechnology provides new tools for the modulation of DC activity in vivo and the therapeutic induction of antigenspecific tolerance in immune-mediated disorders. Open QuestionsAlthough DC populations that promote the development of forkhead box P3-positive (FoxP3 þ ) regulatory T cells (Tregs) have been identified, it is not yet clear whether these populations constitute separate tolerogenic DC lineages or represent alternative activation or maturation states of other DC populations. What are the different molecular pathways that control the DC's ability to prime effector or tolerogenic T-cell responses?There is an unmet clinical need for the development of methods for the efficient and consistent generation of tolerogenic DCs in vitro and in vivo that can be implemented in large-scale clinical setups.Dendritic cells (DCs) are professional antigen-presenting cells (APCs) that control the activation and polarization of T cells into specific lineages and, consequently, the generation of antigen-specific antibody and T-cell responses. 1 In the context of an infectious challenge, the induction of pathogenspecific immune responses provides protective immunity to fight the infection. However, in the context of autoimmune diseases DCs regulate the balance between pathogenic and regulatory immune mechanisms, controlling disease onset and progression. Thus, DCs have a central role in the control of the adaptive immune response to pathogens and selftissues and therefore constitute potential targets for the therapeutic modulation of the immune response. In this review, we discus the role of DCs in autoimmune diseases, with a special emphasis on their role in the modulation of central nervous system (CNS) inflammation in MS. Received 12.6.14; accepted 23.6.14; Edited by H-U Simon; published online 29.8.14 Abbreviations: A...

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Plasmacytoid Dendritic Cells: Recent Progress and Open Questions

Cited by 529 publications

References 151 publications

Self‐priming determines high type I IFN production by plasmacytoid dendritic cells

Self‐priming determines high type I IFN production by plasmacytoid dendritic cells

Recent insights into the implications of metabolism in plasmacytoid dendritic cell innate functions: Potential ways to control these functions

Role and therapeutic value of dendritic cells in central nervous system autoimmunity

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