IFN Regulatory Factor-1 Bypasses IFN-Mediated Antiviral Effects through Viperin Gene Induction

Stirnweiß, Anja; Ksienzyk, Antje; Klages, Katjana; Rand, Ulfert; Grashoff, Martina; Hauser, Hansjörg; Kröger, Andrea

doi:10.4049/jimmunol.0902264

Cited by 114 publications

(103 citation statements)

References 35 publications

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“…& 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim www.eji-journal.eu IRF1 BS was in the promoter sequence of two other genes known to be regulated by IRF1: VCAM-1 and Viperin [24,25]. TESS analysis confirmed the presence of the IRF1 BS also in the promoter of these additional target genes (Fig.…”

mentioning

confidence: 66%

“…We found a putative IRF1 binding site (BS) of six nucleotides (AAGTGA) between À1470 and À1476 nucleotides. To reinforce this data, we investigated if the same IRF1 BS was in the promoter sequence of two other genes known to be regulated by IRF1: VCAM-1 and Viperin [24,25]. TESS analysis confirmed the presence of the IRF1 BS also in the promoter of these additional target genes (Fig.…”

Section: Ox40 Triggering On Treg Cells Leads To Interferon Regulatorymentioning

confidence: 84%

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Intratumor OX40 stimulation inhibits IRF1 expression and IL‐10 production by Treg cells while enhancing CD40L expression by effector memory T cells

et al. 2011

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Treg cells maintain the tumor microenvironment in an immunosuppressive state preventing an effective anti-tumor immune response. A possible strategy to overcome Treg-cell suppression focuses on OX40, a costimulatory molecule expressed constitutively by Treg cells while being induced in activated effector T cells. OX40 stimulation, by the agonist mAb OX86, inhibits Treg-cell suppression and boosts effector T-cell activation. Here we uncover the mechanisms underlying the therapeutic activity of OX86 treatment dissecting its distinct effects on Treg and on effector memory T (Tem) cells, the most abundant CD4 1 populations strongly expressing OX40 at the tumor site. In response to OX86, tumor-infiltrating Treg cells produced significantly less interleukin 10 (IL-10), possibly in relation to a decrease in the transcription factor interferon regulatory factor 1 (IRF1). Tem cells responded to OX86 by upregulating surface CD40L expression, providing a licensing signal to DCs. The CD40L/CD40 axis was required for Tem-cellmediated in vitro DC maturation and in vivo DC migration. Accordingly, OX86 treatment was no longer therapeutic in CD40 KO mice. In conclusion, following OX40 stimulation, blockade of Treg-cell suppression and enhancement of the Tem-cell adjuvant effect both concurred to free DCs from immunosuppression and activate the immune response against the tumor. 3615The tumor microenvironment is characterized by an immunosuppressive cytokine milieu, which promotes immune tolerance and tumor growth. Treg cells secrete interleukin 10 (IL-10), which plays a critical role in suppressing immune responses and in particular the maturation of fully competent DCs [13][14][15]. Among tumor-infiltrating Teff cells, the subpopulation of effector memory T (Tem) cells is the most abundant. Tem cells are CD4 1 CD44 high CD62L low lymphocytes excluded from resting lymph nodes and mainly localized in peripheral tissues; upon stimulation they rapidly activate and secrete effector cytokines like IFN-g, but they have limited proliferative capacity [16]. In experimental models of immune activation, Tem cells constitutively express CD40L at levels sufficient to induce DC activation in an antigen-independent manner [17]. The CD40/CD40L axis is crucial for DC maturation and the subsequent T-cell priming. However in the tumor microenvironment this costimulatory pathway is often dampened, thus impairing the generation of an efficient anti-tumor immune response [18,19].In this study we have investigated the mechanisms by which OX86 modulates Treg-and Teff-cell functions and their reciprocal interactions with DCs at the tumor site. We propose a model of the tumor microenvironment in which, after OX86 treatment, DCs receive a lower IL-10-mediated inhibition by Treg cells on the one hand, and a stronger stimulation from Tem cells, via the CD40/CD40L axis, on the other. In this favorable condition, DCs acquire a stronger migratory ability toward the draining LNs (dLNs), thus inducing a specific anti-tumor immune response. ResultsIntratumoral ...

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confidence: 66%

Section: Ox40 Triggering On Treg Cells Leads To Interferon Regulatorymentioning

confidence: 84%

Intratumor OX40 stimulation inhibits IRF1 expression and IL‐10 production by Treg cells while enhancing CD40L expression by effector memory T cells

et al. 2011

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“…The Influenza virus PR8M which is closely related to the Mount Sinai strain of A/PR/8/34 (H1N1) was obtained from Dr. K. Schughart, Helmholtz Centre for Infection Research, and was propagated in the chorio-allantoic cavity of ten days old embryonated chicken eggs for 48h at 37 0 C (Blazejewska et al, 2011). The vesicular stomatitis virus (VSV) Indiana strain (Stirnweiss et al, 2010) was propagated in Vero B4 cells. Titers were determined by plaques assays on Vero B4 cells.…”

Section: Virusesmentioning

confidence: 99%

Mouse CMV infection delays antibody class switch upon an unrelated virus challenge

Marandu¹,

Finsterbusch²,

Kröger³

et al. 2014

Experimental Gerontology

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“…In mammals, viperin was characterized as one of IFN-inducible antiviral effectors (Carlton-Smith and Elliott, 2012;Fitzgerald, 2011;Helbig et al, 2011;Jiang et al, 2008;Mattijssen and Pruijn, 2012;Overby et al, 2009;Quraishi et al, 2010), and its expression regulation has been investigated in mammals (Boudinot et al, 2000;Chan et al, 2008;Chin and Cresswell, 2001;Olofsson et al, 2005;Saitoh et al, 2011;Severa et al, 2006;Stirnweiss et al, 2010). However, this information in fish is still unclear.…”

Section: Discussionmentioning

confidence: 99%

“…In addition, the activation of viperin mRNA accumulation by HCMV does not require the action of IFN and expression of viral genes (Zhu et al, 1997), indicating that there is IFN-independent pathways for induction of viperin. Another report showed that IRF-1 is required for IFN-independent viperin induction by vesicular stomatitis virus (VSV) but not by Newcastle disease virus and not by a VSV mutant that is unable to block IFN expression and secretion (Stirnweiss et al, 2010). These studies suggest that the expression regulation of viperin gene seems to be complex.…”

Section: Introductionmentioning

confidence: 98%

Fish viperin exerts a conserved antiviral function through RLR-triggered IFN signaling pathway

Wang

Zhang

Liu

et al. 2014

Developmental & Comparative Immunology

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IFN Regulatory Factor-1 Bypasses IFN-Mediated Antiviral Effects through Viperin Gene Induction

Abstract: Material

Cited by 114 publications

References 35 publications

Intratumor OX40 stimulation inhibits IRF1 expression and IL‐10 production by Treg cells while enhancing CD40L expression by effector memory T cells

Intratumor OX40 stimulation inhibits IRF1 expression and IL‐10 production by Treg cells while enhancing CD40L expression by effector memory T cells

Mouse CMV infection delays antibody class switch upon an unrelated virus challenge

Fish viperin exerts a conserved antiviral function through RLR-triggered IFN signaling pathway

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