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

Domizio, Jérémy Di; Blum, Ariane; Gallagher-Gambarelli, Maighread; Molens, Jean-Paul; Chaperot, Laurence; Plumas, Joël

doi:10.1182/blood-2009-04-216770

Cited by 95 publications

(96 citation statements)

References 38 publications

(42 reference statements)

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“…So-called "reverse signaling" through cell surface receptors [e.g., GITR (28)] activates the noncanonical NF-κB pathway, which in synergy with IFN-α induces IDO in murine pDCs, presumably through STAT1 phosphorylation (18). In human pDC, it appears that PI3K-p38 MAPK mediated phosphorylation of STAT1 can occur independently of type I interferons after TLR stimulation (43,44). Therefore, based on our data and others' (15) we speculate that direct TLR activation of STAT1 may bypass the requirement for IFN signaling, and p52/ RelB may act in synergy with or facilitate STAT1 binding to IFNstimulated response element or IFN-γ-activated sequence elements for IDO induction (Fig.…”

Section: Resultsmentioning

confidence: 99%

Activation of the noncanonical NF-κB pathway by HIV controls a dendritic cell immunoregulatory phenotype

Manches

Fernandez

Plumas

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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HIV modulates plasmacytoid dendritic cell (pDC) activation via Tolllike receptor 7, inducing type I IFN and inflammatory cytokines. Simultaneously, pDCs up-regulate the expression of indoleamine 2,3 dioxygenase (IDO), which is essential for the induction of regulatory T cells (Tregs), which function to down-modulate immune activation. Here we demonstrate the crucial importance of the noncanonical NF-κB pathway in the establishment of this immunoregulatory phenotype in pDCs. In response to HIV, the noncanonical NF-κB pathway directly induces IDO and involves the recruitment of TNF receptorassociated factor-3 to the Toll-like receptor/MyD88 complex, NF-κB-inducing kinase-dependent IκB kinase-α activation, and p52/RelB nuclear translocation. We also show that pDC-induced Tregs can inhibit conventional DC (cDC) maturation partially through cytotoxic T-lymphocyte antigen (CTLA)-4 engagement. Furthermore, CTLA-4 induces IDO in cDCs in a NF-κB-inducing kinase-dependent way. These CTLA-4-conditioned cDCs can in turn induce Treg differentiation in an IDO-dependent manner. Thus, the noncanonical NF-κB pathway is integral in controlling immunoregulatory phenotypes of both pDCs and cDCs.

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Section: Resultsmentioning

confidence: 99%

Activation of the noncanonical NF-κB pathway by HIV controls a dendritic cell immunoregulatory phenotype

Manches

Fernandez

Plumas

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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“…In chronically HIV-1-infected individuals, partial activation of DCs (characterized by the upregulation of CD40/CD86 and by spontaneous production of proinflammatory cytokines/chemokines) (63-65) is observed, likely because of the presence of proinflammatory cytokines and TLR ligands, which are abundant because of microbial translocation (10,66,67). This partial activation of DCs likely contributes to increased activation of persistent herpes virus-specific CD4 + T cells during chronic HIV-1 infection (12,13).…”

Section: Discussionmentioning

confidence: 99%

CD8+ T Cells Are Activated in an Antigen-Independent Manner in HIV-Infected Individuals

Bastidas

Graw

Smith

et al. 2014

The Journal of Immunology

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Hyperactivation of T cells, particularly of CD8+ T cells, is a hallmark of chronic HIV 1 (HIV-1) infection. Little is known about the antigenic specificities and the mechanisms by which HIV-1 causes activation of CD8+ T cells during chronic infection. We report that CD8+ T cells were activated during in vivo HIV-1 replication irrespective of their Ag specificity. Cytokines present during untreated HIV-1 infection, most prominently IL-15, triggered proliferation and expression of activation markers in CD8+ T cells, but not CD4+ T cells, in the absence of TCR stimulation. Moreover, LPS or HIV-1–activated dendritic cells (DCs) stimulated CD8+ T cells in an IL-15–dependent but Ag-independent manner, and IL-15 expression was highly increased in DCs isolated from viremic HIV-1 patients, suggesting that CD8+ T cells are activated by inflammatory cytokines in untreated HIV-1 patients independent of Ag specificity. This finding contrasts with CD4+ T cells whose in vivo activation seems biased toward specificities for persistent Ags. These observations explain the higher abundance of activated CD8+ T cells compared with CD4+ T cells in untreated HIV-1 infection.

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“…Increased susceptibility of IRF-7-deficient mice to viruses such as West Nile virus, Chikungunya virus, and SINV demonstrates the central importance of IRF-7 in orchestrating IFN signaling (44,47,(76)(77)(78). Noncanonically, IRF-1, -3, and -7 can upregulate ISG expression in the absence of measurable IFN (48,(79)(80)(81)(82). Utilization of noncanonical, STAT1-independent antiviral signaling by neurons has been demonstrated in neurons during measles virus, WEEV, and St. Louis encephalitis virus infection (49,83).…”

Section: Figmentioning

confidence: 99%

Differentiation of Neurons Restricts Arbovirus Replication and Increases Expression of the Alpha Isoform of IRF-7

Schultz

Vernon

Griffin

2015

J Virol

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Susceptibility to alphavirus infection is age dependent, and host maturation is associated with decreased virus replication and less severe encephalitis. To identify factors associated with maturation-dependent restriction of virus replication, we studied AP-7 rat olfactory bulb neuronal cells, which can differentiate in vitro. Differentiation was associated with a 150-to 1,000-fold decrease in replication of the alphaviruses Sindbis virus and Venezuelan equine encephalitis virus, as well as La Crosse bunyavirus. Differentiation delayed synthesis of SINV RNA and protein but did not alter the susceptibility of neurons to infection or virion maturation. Additionally, differentiation slowed virus-induced translation arrest and death of infected cells. Differentiation of uninfected AP-7 neurons was associated with changes in expression of antiviral genes. Expression of key transcription factors was increased, including interferon regulatory factor 3 and 7 (IRF-3 and IRF-7) and STAT-1, suggesting that neuronal maturation may enhance the capacity for antiviral signaling upon infection. IRF-7 produced by undifferentiated AP-7 neurons was exclusively the short dominant negative ␥-isoform, while that produced by differentiated neurons was the full-length ␣-isoform. A similar switch in IRF-7 isoforms also occurred in the brains of maturing C57BL/6J mice. Silencing of IRF expression did not improve virus multiplication in differentiated neurons. Therefore, neuronal differentiation is associated with upregulation of transcription factors that activate antiviral signaling, but this alone does not account for maturation-dependent restriction of virus replication. IMPORTANCEViral encephalomyelitis is an important cause of age-dependent morbidity and mortality. Because mature neurons are not readily regenerated, recovery from encephalitis suggests that mature neurons utilize unique antiviral mechanisms to block infection and/or clear virus. To identify maturational changes in neurons that may improve outcome, we compared immature and mature cultured neurons for susceptibility to three encephalitic arboviruses and found that replication of Old World and New World alphaviruses and a bunyavirus was reduced in mature compared to immature neurons. Neuronal maturation was associated with increased baseline expression of interferon regulatory factor 3 and 7 mRNAs and production of distinct isoforms of interferon regulatory factor 7 protein. Overall, our studies identified maturational changes in neurons that likely contribute to assembly of immunoregulatory factors prior to infection, a more rapid antiviral response, increased resistance to virus infection, and improved survival. Development of age-dependent resistance to fatal disease is a characteristic of many virus infections of the central nervous system (CNS) (1-9). We have used Sindbis virus (SINV), the prototype alphavirus in the family Togaviridae, as a model system to understand maturation-mediated restriction of virus multiplication in neurons. SINV preferentially i...

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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

Cited by 95 publications

References 38 publications

Activation of the noncanonical NF-κB pathway by HIV controls a dendritic cell immunoregulatory phenotype

Activation of the noncanonical NF-κB pathway by HIV controls a dendritic cell immunoregulatory phenotype

CD8+ T Cells Are Activated in an Antigen-Independent Manner in HIV-Infected Individuals

Differentiation of Neurons Restricts Arbovirus Replication and Increases Expression of the Alpha Isoform of IRF-7

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