Plasmacytoid Dendritic Cells Promote Host Defense against Acute Pneumovirus Infection via the TLR7–MyD88-Dependent Signaling Pathway

Davidson, Sophia; Kaiko, Gerard E.; Loh, Zhixuan; Lalwani, Amit; Zhang, Vivian; Spann, Kirsten; Foo, Shen Yun; Hansbro, Nicole G.; Uematsu, Satoshi; Akira, Shizuo; Matthaei, Klaus I.; Rosenberg, Helene F.; Foster, Paul S.; Phipps, Simon

doi:10.4049/jimmunol.1002635

Cited by 85 publications

(106 citation statements)

References 61 publications

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“…This is one of several mechanisms by which RV infection might precipitate acute asthma exacerbations. Animal models support this hypothesis, with multiple reports that pDC function to inhibit immunopathology associated with both allergic airway inflammation and viral lung infections (41)(42)(43)(44). Further studies are clearly required using asthmatic and atopic cohorts; these investigations must, however, take into consideration the studies of Grayson et al (45) and Subrata et al (5), who describe type-I IFN induction of higher expression of the high-affinity IgE receptor (FcεRI) on DC and monocytes.…”

Section: Discussionmentioning

confidence: 99%

Innate IFNs and Plasmacytoid Dendritic Cells Constrain Th2 Cytokine Responses to Rhinovirus: A Regulatory Mechanism with Relevance to Asthma

Pritchard

Carroll

Burel

et al. 2012

The Journal of Immunology

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Human rhinoviruses (RV) cause only minor illness in healthy individuals, but can have deleterious consequences in people with asthma. This study sought to examine normal homeostatic mechanisms regulating adaptive immunity to RV in healthy humans, focusing on effects of IFN-αβ and plasmacytoid dendritic cells (pDC) on Th2 immune responses. PBMC were isolated from 27 healthy individuals and cultured with RV16 for up to 5 d. In some experiments, IFN-αβ was neutralized using a decoy receptor that blocks IFN signaling, whereas specific dendritic cell subsets were depleted from cultures with immune-magnetic beads. RV16 induced robust expression of IFN-α, IFN-β, multiple IFN-stimulated genes, and T cell-polarizing factors within the first 24 h. At 5 d, the production of memory T cell-derived IFN-γ, IL-10, and IL-13, but not IL-17A, was significantly elevated. Neutralizing the effects of type-I IFN with the decoy receptor B18R led to a significant increase in IL-13 synthesis, but had no effect on IFN-γ synthesis. Depletion of pDC from RV-stimulated cultures markedly inhibited IFN-α secretion, and led to a significant increase in expression and production of the Th2 cytokines IL-5 (p = 0.02), IL-9 (p < 0.01), and IL-13 (p < 0.01), but had no effect on IFN-γ synthesis. Depletion of CD1c+ dendritic cells did not alter cytokine synthesis. In healthy humans, pDC and the IFN-αβ they secrete selectively constrain Th2 cytokine synthesis following RV exposure in vitro. This important regulatory mechanism may be lost in asthma; deficient IFN-αβ synthesis and/or pDC dysfunction have the potential to contribute to asthma exacerbations during RV infections.

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Section: Discussionmentioning

confidence: 99%

Innate IFNs and Plasmacytoid Dendritic Cells Constrain Th2 Cytokine Responses to Rhinovirus: A Regulatory Mechanism with Relevance to Asthma

Pritchard

Carroll

Burel

et al. 2012

The Journal of Immunology

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“…We have demonstrated that the immediate response to low-dose PVM is TLR7 dependent, and that TLR7 on pDCs mediates the early IFN response to control viral spread ( fig. 2) [114]. In the absence of an early antiviral response, TLR7 deficiency leads to airway epithelial cell sloughing and denudation of the basement membrane.…”

Section: Regulation Of Tlr7-mediated Responsesmentioning

confidence: 99%

The plasmacytoid dendritic cell: at the cross-roads in asthma

et al. 2013

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The onset, progression and exacerbations of asthma are frequently associated with viral infections of the lower respiratory tract. An emerging paradigm suggests that this relationship may be underpinned by a defect in the host's antiviral response, typified by the impaired production of type I and type III interferons (IFNs). The failure to control viral burden probably causes damage to the lung architecture and contributes to an aberrant immune response, which together compromise lung function.Although a relatively rare cell type, the plasmacytoid dendritic cell dedicates much of its transcriptome to the synthesis of IFNs and is pre-armed with virus-sensing pattern recognition receptors. Thus, plasmacytoid dendritic cells are specialised to ensure early viral detection and the rapid induction of the antiviral state to block viral replication and spread. In addition, plasmacytoid dendritic cells can limit immunopathology, and promote peripheral tolerance to prevent allergic sensitisation to harmless antigens, possibly through the induction of regulatory T-cells. Thus, this enigmatic cell may lie at an important intersection, orchestrating the immediate phase of antiviral immunity to effect viral clearance while regulating tolerance.Here, we review the evidence to support the hypothesis that a primary defect in plasmacytoid dendritic function may underlie the development of asthma. @ERSpublications A review of the evidence on the role of plasmacytoid dendritic function in the development of asthma

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“…At 84 d of age, mice were lightly anesthetized with isofluorane and inoculated with pneumonia virus of mice (PVM) (10 PFU) strain J3666 (22). Mice were euthanized 6 d post-PVM infection.…”

Section: Pneumonia Virus Of Mice Infectionmentioning

confidence: 99%

Regulatory T Cells Prevent Inducible BALT Formation by Dampening Neutrophilic Inflammation

Foo

Zhang

Lalwani

et al. 2015

The Journal of Immunology

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Inducible BALT (iBALT) can amplify pulmonary or systemic inflammatory responses to the benefit or detriment of the host. We took advantage of the age-dependent formation of iBALT to interrogate the underlying mechanisms that give rise to this ectopic, tertiary lymphoid organ. In this study, we show that the reduced propensity for weanling as compared with neonatal mice to form iBALT in response to acute LPS exposure is associated with greater regulatory T cell expansion in the mediastinal lymph nodes. Ab- or transgene-mediated depletion of regulatory T cells in weanling mice upregulated the expression of IL-17A and CXCL9 in the lungs, induced a tissue neutrophilia, and increased the frequency of iBALT to that observed in neonatal mice. Remarkably, neutrophil depletion in neonatal mice decreased the expression of the B cell active cytokines, a proliferation-inducing ligand and IL-21, and attenuated LPS-induced iBALT formation. Taken together, our data implicate a role for neutrophils in lymphoid neogenesis. Neutrophilic inflammation is a common feature of many autoimmune diseases in which iBALT are present and pathogenic, and hence the targeting of neutrophils or their byproducts may serve to ameliorate detrimental lymphoid neogenesis in a variety of disease contexts.

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Plasmacytoid Dendritic Cells Promote Host Defense against Acute Pneumovirus Infection via the TLR7–MyD88-Dependent Signaling Pathway

Cited by 85 publications

References 61 publications

Innate IFNs and Plasmacytoid Dendritic Cells Constrain Th2 Cytokine Responses to Rhinovirus: A Regulatory Mechanism with Relevance to Asthma

Innate IFNs and Plasmacytoid Dendritic Cells Constrain Th2 Cytokine Responses to Rhinovirus: A Regulatory Mechanism with Relevance to Asthma

The plasmacytoid dendritic cell: at the cross-roads in asthma

Regulatory T Cells Prevent Inducible BALT Formation by Dampening Neutrophilic Inflammation

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