Vaccinia Virus-Mediated Inhibition of Type I Interferon Responses Is a Multifactorial Process Involving the Soluble Type I Interferon Receptor B18 and Intracellular Components

Waibler, Zoe; Anzaghe, Martina; Frenz, Theresa; Schwantes, Astrid; Pöhlmann, Christopher; Ludwig, Holger; Palomo-Otero, Marcos; Alcamı́, Antonio; Sutter, Gerd; Kalinke, Ulrich

doi:10.1128/jvi.01617-08

Cited by 70 publications

(80 citation statements)

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“…In addition to MHC molecules, other factors involved in antigen processing, such as TAP and the lysosomal membrane permeabilization components of proteasomes are regulated by IFN. Thus, IFNAR-triggering promotes the switch from proteasome to immuno-proteasome [36,37].In a previous study, we found in an in vitro setting that MVA infection can enhance expression of activation markers and costimulatory molecules on DC, whereas VACV infection effectively inhibited DC activation [16]. Here, we additionally demonstrated that MVA infection induced IFNAR-dependently co-stimulation in vivo that in turn indirectly influenced T-cell priming and expansion of CD8 1 T cells.…”

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confidence: 59%

“…VACV deploys a multitude of different strategies to evade immune surveillance. Most notably, VACV efficiently inhibits induction of IFN [15,16], whereas closely related MVA, which was attenuated by more than 570 in vitro passages of chorioallantois vaccinia virus Ankara on chicken embryo fibroblasts, shows several genomic alterations conferring loss of IFN inhibitors [16][17][18].Here, we demonstrate that IFNAR-signaling of T cells critically promotes MVA-induced CD8 1 T-cell proliferation and clonal expansion, whereas upon VACV infection a less stringent correlation was found. MVA-induced T-cell expansion was not associated with a reduced capacity of IFNAR-deficient T cells to get activated but rather with a lack of survival signal.…”

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confidence: 67%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

“…Nevertheless, little is known about cellular and viral mechanisms that are associated with high immunogenicity of MVA. Considering the ability of MVA to induce IFN responses in the serum, whereas VACV does not [16], these two closely related virus strains are an ideal model to study the impact of virus-induced IFN on adaptive immunity.Previously, it was shown that upon LCMV infection expansion of gp33-specific T cells was dependent on IFNAR-triggering of T cells, whereas after VACV gp33 infection expansion of specific T cells was less IFNAR-dependent [12]. To further elaborate on this observation, in a first step we performed adoptive transfer experiments.…”

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confidence: 99%

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Concomitant type I IFN receptor‐triggering of T cells and of DC is required to promote maximal modified vaccinia virus Ankara‐induced T‐cell expansion

et al. 2010

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Clinical Infection Research; a joint venture between the Medical School Hannover and the Helmholtz Centre for Infection Research, Braunschweig; Hannover, Germany Virus-induced expansion of CD8 1 T cells may be promoted by type I IFN receptor (IFNAR)-triggering of T cells, depending on the pathogen tested. We studied modified vaccinia virus Ankara (MVA), a promising vaccine vector candidate, which was derived from conventional vaccinia virus (VACV) by more than 570 consecutive in vitro passages. In adoptive transfer experiments, we verified that VACV expressing the gp33 epitope of lymphocytic choriomeningitis virus (VACV gp33 ) induced largely IFNAR-independent expansion of gp33-specific T cells. On the contrary, MVA gp33 -induced T-cell expansion was IFNAR dependent. Interestingly, under the latter conditions, T-cell activation was IFNAR independent, whereas T-cell apoptosis was enhanced in the absence of IFNAR. To address whether MVA-induced T-cell expansion was solely affected by IFNAR-triggering of T cells, expansion of endogenous T cells was studied in conditional mice with a T-cell-or DC-specific IFNAR deletion. Interestingly, both mouse strains showed moderately reduced T-cell expansion, whereas mice with a combined T-cell-and DC-specific IFNAR ablation showed massively reduced T-cell expansion similar to that of IFNAR À/À mice. These results are compatible with the model that IFN-inducing viruses such as MVA confer virus-specific CD8 1 T-cell expansion by concomitant IFNAR-triggering of DC and of T cells.Key words: CD8 1 T-cell expansion . Modified vaccinia virus Ankara . Type I IFN IntroductionInfection with many different viruses induces rapid type I IFN responses that are detectable in serum within hours. IFN constitutes a family of cytokines with 14 IFN-a, one IFN-b subtype, and a number of other subclasses including . All IFN bind to one common heterodimeric receptor consisting of an a-chain (type I IFN receptor, IFNAR1) and a b-chain (IFNAR2). IFNAR-triggering results in phosphorylation of STAT1 and STAT2 transcription factors and the induction of at least 200 different target genes [2,3]. Although most cell lines show IFN expression upon in vitro infection, [7][8][9]. In particular, several studies reported IFN-mediated effects on T-cell responses [10,11]. In one report, lack of direct IFNAR-signaling on the level of CD8 1 T cells was associated with reduced expansion of gp33-specific T cells upon infection with lymphocytic choriomeningitis virus (LCMV). This phenomenon was less pronounced upon infection with VACV gp33 [12]. Interestingly, instead of enhancing T-cell function, IFN can also lead to T-cell attrition or activation induced cell death [13,14].To further study the impact of virus-induced IFN on the stimulation of virus-specific T-cell responses, we analyzed expansion of antigen-specific T cells upon infection with two closely related viruses, vaccinia virus (VACV) and modified vaccinia virus Ankara (MVA), which upon infection either suppress or induce IFN responses, respectively. VACV d...

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confidence: 59%

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confidence: 67%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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confidence: 99%

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Concomitant type I IFN receptor‐triggering of T cells and of DC is required to promote maximal modified vaccinia virus Ankara‐induced T‐cell expansion

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Feeder‐Free Reprogramming of Human Fibroblasts with Messenger RNA

Warren

Wang

2013

CP Stem Cell Biology

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This unit describes a feeder‐free protocol for deriving induced pluripotent stem cells (iPSCs) from human fibroblasts by transfection of synthetic mRNA. The reprogramming of somatic cells requires transient expression of a set of transcription factors that collectively activate an endogenous gene regulatory network specifying the pluripotent phenotype. The necessary ectopic factor expression was first effected using retroviruses; however, as viral integration into the genome is problematic for cell therapy applications, the use of footprint‐free vectors such as mRNA is increasingly preferred. Strong points of the mRNA approach include high efficiency, rapid kinetics, and obviation of a clean‐up phase to purge the vector. Still, the method is relatively laborious and has, up to now, involved the use of feeder cells, which brings drawbacks including poor applicability to clinically oriented iPSC derivation. Using the methods described here, mRNA reprogramming can be performed without feeders at much‐reduced labor and material costs relative to established protocols. Curr. Protoc. Stem Cell Biol. 27:4A.6.1‐4A.6.27. © 2013 by John Wiley & Sons, Inc.

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cGMP Generation of Human Induced Pluripotent Stem Cells with Messenger RNA

Zhao

Warren³

et al. 2016

CP Stem Cell Biology

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Reprogramming somatic cells to generate induced pluripotent stem cells (iPSCs) has presented the biomedical community with a powerful platform to develop new models for human disease. To fully realize the promise of this technology in cell therapy and regenerative medicine, creating iPSCs under current Good Manufacture Practice (cGMP) conditions is paramount. Some reports have described efforts in this regard, resulting in iPSC lines that are cGMP compliant. The technology developed at Allele Biotechnology for footprint‐free, feeder‐free, and xeno‐free reprogramming using only mRNA is very suitable for creating iPSC lines through an established cGMP process. This technology has resulted in a licensing agreement between Allele Biotechnology and Ocata (formerly ACT, now a wholly owned division of Astellas) for clinical applications. All reagents and vessels are certified as cGMP‐produced, all equipment and software are certifiable, and all procedures are carried out in Industry ISO 7 or Class 10,000‐grade cleanrooms. In this revised version of the unit, we describe the core improvements to implement steps toward cGMP‐compliant generation of iPSCs. Recreating a process close to cGMP production in academic research will make these findings more applicable to translational research. © 2016 by John Wiley & Sons, Inc.

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Vaccinia Virus-Mediated Inhibition of Type I Interferon Responses Is a Multifactorial Process Involving the Soluble Type I Interferon Receptor B18 and Intracellular Components

Abstract: Poxviruses such as virulent vaccinia virus (VACV) strain

Cited by 70 publications

References 63 publications

Concomitant type I IFN receptor‐triggering of T cells and of DC is required to promote maximal modified vaccinia virus Ankara‐induced T‐cell expansion

Concomitant type I IFN receptor‐triggering of T cells and of DC is required to promote maximal modified vaccinia virus Ankara‐induced T‐cell expansion

Feeder‐Free Reprogramming of Human Fibroblasts with Messenger RNA

cGMP Generation of Human Induced Pluripotent Stem Cells with Messenger RNA

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