Plasmacytoid dendritic cells control TLR7 sensitivity of naive B cells via type I IFN

ABSTRACT Epstein-Barr virus (EBV), a human herpesvirus, encodes 44 microRNAs (miRNAs), which regulate many genes with various functions in EBV-infected cells. Multiple target genes of the EBV miRNAs have been identified, some of which play important roles in adaptive antiviral immune responses. Using EBV mutant derivatives, we identified additional roles of viral miRNAs in governing versatile type I interferon (IFN) responses upon infection of human primary mature B cells. We also found that Epstein-Barr virus-encoded small RNAs (EBERs) and LF2, viral genes with previously reported functions in inducing or regulating IFN-I pathways, had negligible or even contrary effects on secreted IFN-α in our model. Data mining and Ago PAR-CLIP experiments uncovered more than a dozen previously uncharacterized, direct cellular targets of EBV miRNA associated with type I IFN pathways. We also identified indirect targets of EBV miRNAs in B cells, such as TRL7 and TLR9, in the prelatent phase of infection. The presence of epigenetically naive, non-CpG methylated viral DNA was essential to induce IFN-α secretion during EBV infection in a TLR9-dependent manner. In a newly established fusion assay, we verified that EBV virions enter a subset of plasmacytoid dendritic cells (pDCs) and determined that these infected pDCs are the primary producers of IFN-α in EBV-infected peripheral blood mononuclear cells. Our findings document that many EBV-encoded miRNAs regulate type I IFN response in newly EBV infected primary human B cells in the prelatent phase of infection and dampen the acute release of IFN-α in pDCs upon their encounter with EBV. IMPORTANCE Acute antiviral functions of all nucleated cells rely on type I interferon (IFN-I) pathways triggered upon viral infection. Host responses encompass the sensing of incoming viruses, the activation of specific transcription factors that induce the transcription of IFN-I genes, the secretion of different IFN-I types and their recognition by the heterodimeric IFN-α/β receptor, the subsequent activation of JAK/STAT signaling pathways, and, finally, the transcription of many IFN-stimulated genes (ISGs). In sum, these cellular functions establish a so-called antiviral state in infected and neighboring cells. To counteract these cellular defense mechanisms, viruses have evolved diverse strategies and encode gene products that target antiviral responses. Among such immune-evasive factors are viral microRNAs (miRNAs) that can interfere with host gene expression. We discovered that multiple miRNAs of Epstein-Barr virus (EBV) control over a dozen cellular genes that contribute to the antiviral states of immune cells, specifically B cells and plasmacytoid dendritic cells (pDCs). We identified the viral DNA genome as the activator of IFN-α and question the role of abundant EBV EBERs, that, contrary to previous reports, do not have an apparent inducing function in the IFN-I pathway early after infection.

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Plasmacytoid Dendritic Cells Control TLR7 Sensitivity of Naive B Cells via Type I IFN

The Journal of Immunology ◽

10.4049/jimmunol.174.7.4043 ◽

2005 ◽

Vol 174 (7) ◽

pp. 4043-4050 ◽

Cited By ~ 231

Author(s):

Isabelle Béatrice Bekeredjian-Ding ◽

Moritz Wagner ◽

Veit Hornung ◽

Thomas Giese ◽

Max Schnurr ◽

...

Keyword(s):

Dendritic Cells ◽

B Cells ◽

Plasmacytoid Dendritic Cells ◽

Type I ◽

Type I Ifn

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PLASMACYTOID DENDRITIC CELLS FUNCTION IN HIV INFECTION

Clinical & Investigative Medicine ◽

10.25011/cim.v31i4.4808 ◽

2008 ◽

Vol 31 (4) ◽

pp. 13

Author(s):

Martin Hyrcza ◽

Mario Ostrowski ◽

Sandy Der

Keyword(s):

Dendritic Cells ◽

Influenza Virus ◽

Hiv Infection ◽

Gene Transcription ◽

Sendai Virus ◽

Plasmacytoid Dendritic Cells ◽

Type I Interferons ◽

Interferon Response ◽

Type I ◽

Type I Ifn

Plasmacytoid dendritic cells (pDCs) are innate immune cells able to produce large quantities of type I interferons (IFN) when activated. Human immunodeficiency virus (HIV)-infected patients show generalized immune dysfunction characterized in part by chronic interferon response. In this study we investigated the role of dendritic cells inactivating and maintaining this response. Specifically we compared the IFN geneactivity in pDCs in response to several viruses and TLR agonists. We hypothesized that 1) the pattern of IFN gene transcription would differ in pDCs treated with HIV than with other agents, and 2) that pDCs from patients from different stages of disease would respond differently to the stimulations. To test these hypotheses, we obtained pDCs from 15 HIV-infected and uninfected individuals and treated freshly isolated pDCs with either HIV (BAL strain), influenza virus (A/PR/8/34), Sendai virus (Cantell strain), TLR7 agonist(imiquimod), or TLR9 agonist (CpG-ODN) for 6h. Type I IFN gene transcription was monitored by real time qPCRfor IFNA1, A2, A5, A6, A8,A17, B1, and E1, and cytokine levels were assayed by Cytometric Bead Arrays forTNF?, IL6, IL8, IL10, IL1?, and IL12p70. pDC function as determined by these two assays showed no difference between HIV-infected and uninfected patients or between patients with early or chronic infection. Specifically, HIV did notinduce type I IFN gene expression, whereas influenza virus, Sendai virus and imiquimod did. Similarly, HIV failed to induce any cytokine release from pDCs in contrast to influenza virus, Sendai virus and imiquimod, which stimulatedrelease of TNF?, IL6, or IL8. Together these results suggest that the reaction of pDCs to HIV virus is quantitatively different from the response to agents such as virus, Sendai virus, and imiquimod. In addition, pDCs from HIV-infected persons have responses similar to pDCs from uninfected donors, suggesting, that the DC function may not be affected by HIV infection.

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STING-Licensed Macrophages Prime Type I IFN Production by Plasmacytoid Dendritic Cells in the Bone Marrow during Severe Plasmodium yoelii Malaria

PLoS Pathogens ◽

10.1371/journal.ppat.1005975 ◽

2016 ◽

Vol 12 (10) ◽

pp. e1005975 ◽

Cited By ~ 39

Author(s):

Emily Spaulding ◽

David Fooksman ◽

Jamie M. Moore ◽

Alex Saidi ◽

Catherine M. Feintuch ◽

...

Keyword(s):

Bone Marrow ◽

Dendritic Cells ◽

Plasmodium Yoelii ◽

Plasmacytoid Dendritic Cells ◽

Type I ◽

Type I Ifn ◽

Prime Type

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Type I Interferon Inhibition and Dendritic Cell Activation during Gammaherpesvirus Respiratory Infection

Journal of Virology ◽

10.1128/jvi.00360-07 ◽

2007 ◽

Vol 81 (18) ◽

pp. 9778-9789 ◽

Cited By ~ 24

Author(s):

Janet L. Weslow-Schmidt ◽

Nancy A. Jewell ◽

Sara E. Mertz ◽

J. Pedro Simas ◽

Joan E. Durbin ◽

...

Keyword(s):

Dendritic Cells ◽

Dendritic Cell ◽

Cell Activation ◽

Type I Interferon ◽

Plasmacytoid Dendritic Cells ◽

The Body ◽

Type I ◽

Type I Ifn ◽

Dendritic Cell Activation ◽

Murine Gammaherpesvirus

ABSTRACT The respiratory tract is a major mucosal site for microorganism entry into the body, and type I interferon (IFN) and dendritic cells constitute a first line of defense against viral infections. We have analyzed the interaction between a model DNA virus, plasmacytoid dendritic cells, and type I IFN during lung infection of mice. Our data show that murine gammaherpesvirus 68 (γHV68) inhibits type I IFN secretion by dendritic cells and that plasmacytoid dendritic cells are necessary for conventional dendritic cell maturation in response to γHV68. Following γHV68 intranasal inoculation, the local and systemic IFN-α/β response is below detectable levels, and plasmacytoid dendritic cells are activated and recruited into the lung with a tissue distribution that differs from that of conventional dendritic cells. Our results suggest that plasmacytoid dendritic cells and type I IFN have important but independent roles during the early response to a respiratory γHV68 infection. γHV68 infection inhibits type I IFN production by dendritic cells and is a poor inducer of IFN-α/β in vivo, which may serve as an immune evasion strategy.

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Dysregulated miRNome of plasmacytoid dendritic cells from patients with Sjögren’s syndrome is associated with processes at the centre of their function

Rheumatology ◽

10.1093/rheumatology/kez195 ◽

2019 ◽

Vol 58 (12) ◽

pp. 2305-2314 ◽

Cited By ~ 5

Author(s):

Maarten R Hillen ◽

Eleni Chouri ◽

Maojie Wang ◽

Sofie L M Blokland ◽

Sarita A Y Hartgring ◽

...

Keyword(s):

Cell Death ◽

Dendritic Cells ◽

Mammalian Target Of Rapamycin ◽

Plasmacytoid Dendritic Cells ◽

Type I ◽

Large Set ◽

Type I Ifn ◽

Stable Isotope Labelling ◽

Proteomic Approach ◽

Novel Targets

Abstract Objective A considerable body of evidence supports a role for type-I IFN in the pathogenesis of primary SS (pSS). As plasmacytoid dendritic cells (pDCs) are a major source of type-I IFN, we investigated their molecular regulation by measuring expression of a large set of miRNAs. Methods pDCs were isolated from peripheral blood of pSS patients (n = 30) and healthy controls (n = 16) divided into two independent cohorts (discovery and replication). Screening of 758 miRNAs was assessed by an OpenArray quantitative PCR-based technique; replication of a set of identified miRNAs was performed by custom array. Functional annotation of miRNA targets was performed using pathway enrichment. Novel targets of miR-29a and miR-29c were identified using a proteomic approach (stable isotope labelling with amino acids in cell culture). Results In the discovery cohort, 20 miRNAs were differentially expressed in pSS pDCs compared with healthy control pDCs. Of these, differential expression of 10 miRNAs was confirmed in the replication cohort. The dysregulated miRNAs were involved in phosphoinositide 3-kinase-Ak strain transforming and mammalian target of rapamycin signalling, as well as regulation of cell death. In addition, a set of novel protein targets of miR-29a and miR-29c were identified, including five targets that were regulated by both miRs. Conclusion The dysregulated miRNome in pDCs of patients with pSS is associated with aberrant regulation of processes at the centre of pDC function, including type-I IFN production and cell death. As miR-29a and miR-29c are pro-apoptotic factors and several of the novel targets identified here are regulators of apoptosis, their downregulation in patients with pSS is associated with enhanced pDC survival.

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CS16-6. Plasmacytoid Dendritic Cells are infected by Epstein Barr virus and induces TLR- dependent type I IFN production

Cytokine ◽

10.1016/j.cyto.2011.07.411 ◽

2011 ◽

Vol 56 (1) ◽

pp. 106

Author(s):

Martina Severa ◽

Elena Giacomini ◽

Eleni Anastasiadou ◽

Valerie Gafa ◽

Fabiana Rizzo ◽

...

Keyword(s):

Dendritic Cells ◽

Epstein Barr Virus ◽

Plasmacytoid Dendritic Cells ◽

Type I ◽

Type I Ifn ◽

Barr Virus ◽

Epstein Barr ◽

Dependent Type

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The MEK1/2-ERK Pathway Inhibits Type I IFN Production in Plasmacytoid Dendritic Cells

Frontiers in Immunology ◽

10.3389/fimmu.2018.00364 ◽

2018 ◽

Vol 9 ◽

Cited By ~ 9

Author(s):

Vaclav Janovec ◽

Besma Aouar ◽

Albert Font-Haro ◽

Tomas Hofman ◽

Katerina Trejbalova ◽

...

Keyword(s):

Dendritic Cells ◽

Plasmacytoid Dendritic Cells ◽

Type I ◽

Erk Pathway ◽

Type I Ifn

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Wiskott-Aldrich syndrome protein–mediated actin dynamics control type-I interferon production in plasmacytoid dendritic cells

Journal of Experimental Medicine ◽

10.1084/jem.20120363 ◽

2013 ◽

Vol 210 (2) ◽

pp. 355-374 ◽

Cited By ~ 38

Author(s):

Francesca Prete ◽

Marco Catucci ◽

Mayrel Labrada ◽

Stefania Gobessi ◽

Maria Carmina Castiello ◽

...

Keyword(s):

Dendritic Cells ◽

Actin Polymerization ◽

Type I Interferon ◽

Plasmacytoid Dendritic Cells ◽

Actin Dynamics ◽

Type I ◽

Type I Ifn ◽

Wiskott Aldrich Syndrome ◽

Elevated Type ◽

Chronic Activation

Mutations in Wiskott-Aldrich syndrome (WAS) protein (WASp), a regulator of actin dynamics in hematopoietic cells, cause WAS, an X-linked primary immunodeficiency characterized by recurrent infections and a marked predisposition to develop autoimmune disorders. The mechanisms that link actin alterations to the autoimmune phenotype are still poorly understood. We show that chronic activation of plasmacytoid dendritic cells (pDCs) and elevated type-I interferon (IFN) levels play a role in WAS autoimmunity. WAS patients display increased expression of type-I IFN genes and their inducible targets, alteration in pDCs numbers, and hyperresponsiveness to TLR9. Importantly, ablating IFN-I signaling in WASp null mice rescued chronic activation of conventional DCs, splenomegaly, and colitis. Using WASp-deficient mice, we demonstrated that WASp null pDCs are intrinsically more responsive to multimeric agonist of TLR9 and constitutively secrete type-I IFN but become progressively tolerant to further stimulation. By acute silencing of WASp and actin inhibitors, we show that WASp-mediated actin polymerization controls intracellular trafficking and compartmentalization of TLR9 ligands in pDCs restraining exaggerated activation of the TLR9–IFN-α pathway. Together, these data highlight the role of actin dynamics in pDC innate functions and imply the pDC–IFN-α axis as a player in the onset of autoimmune phenomena in WAS disease.

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TLR7 stimulation in human plasmacytoid dendritic cells leads to the induction of early IFN-inducible genes in the absence of type I IFN

Blood ◽

10.1182/blood-2009-04-216770 ◽

2009 ◽

Vol 114 (9) ◽

pp. 1794-1802 ◽

Cited By ~ 67

Author(s):

Jérémy Di Domizio ◽

Ariane Blum ◽

Maighread Gallagher-Gambarelli ◽

Jean-Paul Molens ◽

Laurence Chaperot ◽

...

Keyword(s):

Dendritic Cells ◽

Plasmacytoid Dendritic Cells ◽

Innate Immune ◽

Type I ◽

Type I Ifn ◽

P38mapk Pathway ◽

Inducible Genes ◽

Level Production ◽

Early Phases ◽

Tlr7 Stimulation

On recognition of influenza virus (Flu) by TLR7, plasmacytoid dendritic cells (pDCs) produce type I IFN in significant amounts. Synthetic TLR7 ligands induce the maturation of pDCs, as evidenced by the expression of costimulatory molecules and the production of proinflammatory cytokines; however, they induce only low-level production of IFN-α. To dissect the TLR7 signaling in pDCs and how these different profiles are induced, we studied the effects of 2 TLR7 ligands (Flu and CL097) on the activation of blood-isolated pDCs and the human GEN2.2 pDC cell line. Type I IFN production by pDCs correlates with differential interferon regulatory factor 7 (IRF7) translocation into the nucleus induced by the 2 TLR7 ligands. Surprisingly, with both activators we nevertheless observed the rapid expression of the IFN-inducible genes mxa, cxcl10, and trail within 4 hours of stimulation. This expression, controlled by STAT1 phosphorylation, was independent of type I IFN. STAT1 activation was found to be strictly dependent on the PI3K-p38MAPK pathway, showing a new signaling pathway leading to rapid expression of IFN-inducible genes after TLR7 triggering. Thus, pDCs, through this unusual TLR7 signaling, have the capacity to promptly respond to viral infection during the early phases of the innate immune response.

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