Poly I:CLC Induction of the Interferon System in Mice: An Initial Study of Four Detection Methods

Poast, Joyce; Seidel, H. Martin; Hendricks, Michelle; Haslam, Jennifer A.; Levy, Hilton B.; Baron, Samuel

doi:10.1089/107999002760624260

Cited by 12 publications

(10 citation statements)

References 12 publications

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“…For this reason, we asked whether exposure to exogenous IFN‐I could further enhance the turnover rate of DC populations in normal mice. To this end, we first injected PolyI:C, a potent inducer of IFN‐I 18, 32, into WT and IFNAR KO mice and then analysed the extent of BrdU incorporation 3 days later. As shown in Fig.…”

Section: Resultsmentioning

confidence: 99%

Type I IFN regulate DC turnover in vivo

et al. 2009

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DC are the most potent antigen-presenting cells that recognise signs of infection and serve as the main activators of naïve T cells. We have previously shown that type I IFN (IFN-I) are produced by DC and can act in an autocrine manner to activate DC. In the present study, we have investigated the role of IFN-I in regulating the turnover and lifespan of DC. We found that DC, especially the CD8a 1 subset, from type I IFN receptor knock out (IFNAR KO) mice, display a reduced turnover rate when compared with DC from WT mice, as revealed by BrdU labelling kinetics. In vitro, IFNAR KO BM precursor cells cultured in the presence of GM-CSF generated CD11c 1 DC less efficiently than WT BM, and the IFNAR KO DC that arose displayed reduced migratory ability. Interestingly, splenic DC from IFNAR KO mice exhibited a higher survival rate in short-term culture compared with control DC. Exposure to IFN-I in vivo markedly increased the turnover rate of splenic DC, particularly CD8a 1 DC, which was preceded by a transient induction of apoptosis. In accordance with this, IFN-I stimulated the apoptosis of splenic DC in vitro. Overall, our data indicate that IFN-I are important regulators of DC turnover in vivo and suggest that these cytokines may exert this function through the modulation of multiple processes involving DC apoptosis, proliferation and migration.

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Section: Resultsmentioning

confidence: 99%

Type I IFN regulate DC turnover in vivo

et al. 2009

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“…Plasmacytoid DCs express high levels of IFN-α (37, 38, 39, 40, 41) which has been shown to restrict HSV-1 replication (42, 43). Measurement of type I IFN by ELISA is relatively insensitive (37) so an indirect measure of type I IFN activity was undertaken by measuring the IFN-stimulated gene ISG54 expression by real-time RT-PCR (37). However, we did not observe differences between WT and CXCL10 −/− animals for ISG54 mRNA levels relative to the housekeeping gene β-actin in the BS at either days 5 or 7 p.i.…”

Section: Resultsmentioning

confidence: 99%

Dysregulation of CXCR3 Signaling due to CXCL10 Deficiency Impairs the Antiviral Response to Herpes Simplex Virus 1 Infection

Wuest

Carr

2008

The Journal of Immunology

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The chemokine, CXCL10, chemotactic for NK cells, activated T cells, and dendritic cells is highly expressed during viral infections, including HSV-1. The importance of this chemokine to the control of HSV-1 infection was tested using mice deficient in CXCL10 (CXCL10−/−). Following corneal infection, HSV-1 viral titers were elevated in the nervous system of CXCL10−/− mice, which correlated with defects in leukocyte recruitment including dendritic cells, NK cells, and HSV-1-specific CD8+ T cells to the brain stem. In the absence of NK cells and HSV-1-specific CD8+ T cells in wild-type (WT) or CXCL10−/− mice, similar levels of virus were recovered in the nervous system, suggesting these cells are responsible for the observed defects in the control of viral replication in CXCL10−/− mice. Leukocyte mobilization was also compared between WT, CXCL10−/−, and mice deficient in the only known receptor for CXCL10, CXCR3 (CXCR3 −/−). NK cell mobilization was comparably reduced in both CXCL10−/− and CXCR3−/− mice relative to WT animals. However, the reduction in mobilization of HSV-1-specific CD8+ T cells in CXCL10−/− was not observed in CXCR3−/− mice following HSV-1 infection. The defect was not the result of an alternative receptor for CXCL10, as Ag-specific CD8+ T cell recruitment was not reduced in mice which were deficient in both CXCL10 and CXCR3. Thus, CXCL10 deficiency results in reduced mobilization of HSV-1-specific CD8+ T cells as a result of dysregulation of CXCR3 signaling.

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“…dsRNA ONs are soluble, homogeneous molecules that can be manufactured in a consistent fashion. By contrast, other TLR3-stimulating adjuvants including pIC, polyI:C12U (59), poly I:CLC (60), and PIKA (61) are heterogeneous and may vary between batches in both chemical structure and biological function, particularly with regard to their capacity to promiscuously activate non-TLR3 dependent pathways with unpredictable consequences. The efficacy of a dsRNA ON as an activator of TLR3 depends upon its length and not its nucleotide sequence, in contrast to CpG ODNs that are being tested as TLR9-based adjuvants (62).…”

Section: Discussionmentioning

confidence: 99%

TLR3-Specific Double-Stranded RNA Oligonucleotide Adjuvants Induce Dendritic Cell Cross-Presentation, CTL Responses, and Antiviral Protection

Jelinek

Leonard

Price

et al. 2011

The Journal of Immunology

176

163

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Maturation of dendritic cells (DC) to competent APC is essential for the generation of acquired immunity and is a major function of adjuvants. dsRNA, a molecular signature of viral infection, drives DC maturation by activating TLR3, but the size of dsRNA required to activate DC and the expression patterns of TLR3 protein in DC subsets have not been established. In this article, we show that cross-priming CD8α+ and CD103+ DC subsets express much greater levels of TLR3 than other DC. In resting DC, TLR3 is located in early endosomes and other intracellular compartments but migrates to LAMP1+ endosomes on stimulation with a TLR3 ligand. Using homogeneous dsRNA oligonucleotides (ONs) ranging in length from 25 to 540 bp, we observed that a minimum length of ∼90 bp was sufficient to induce CD86, IL-12p40, IFN-β, TNF-α, and IL-6 expression, and to mature DC into APC that cross-presented exogenous Ags to CD8+ T cells. TLR3 was essential for activation of DC by dsRNA ONs, and the potency of activation increased with dsRNA length and varied between DC subsets. In vivo, dsRNA ONs, in a size-dependent manner, served as adjuvants for the generation of Ag-specific CTL and for inducing protection against lethal challenge with influenza virus when given with influenza nucleoprotein as an immunogen. These results provide the basis for the development of TLR3-specific adjuvants capable of inducing immune responses tailored for viral pathogens.

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Poly I:CLC Induction of the Interferon System in Mice: An Initial Study of Four Detection Methods

Cited by 12 publications

References 12 publications

Type I IFN regulate DC turnover in vivo

Type I IFN regulate DC turnover in vivo

Dysregulation of CXCR3 Signaling due to CXCL10 Deficiency Impairs the Antiviral Response to Herpes Simplex Virus 1 Infection

TLR3-Specific Double-Stranded RNA Oligonucleotide Adjuvants Induce Dendritic Cell Cross-Presentation, CTL Responses, and Antiviral Protection

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