scholarly journals Murine gammaherpesvirus-68 productively infects immature dendritic cells and blocks maturation

2007 ◽  
Vol 88 (7) ◽  
pp. 1896-1905 ◽  
Author(s):  
Romana Hochreiter ◽  
Catherine Ptaschinski ◽  
Steven L. Kunkel ◽  
Rosemary Rochford
Keyword(s):  
Dendritic Cells ◽  
Mhc Class I ◽  
Viral Reactivation ◽  
Class I ◽  
Interleukin 12 ◽  
Murine Gammaherpesvirus ◽  
Immature Dendritic Cells ◽  
Gammaherpesvirus 68 ◽  
Murine Gammaherpesvirus 68 ◽  
Dc Maturation

Many viruses have evolved mechanisms to evade host immunity by subverting the function of dendritic cells (DCs). This study determined whether murine gammaherpesvirus-68 (γHV-68) could infect immature or mature bone-marrow-derived DCs and what effect infection had on DC maturation. It was found that γHV-68 productively infected immature DCs, as evidenced by increased viral titres over time. If DCs were induced to mature by exposure to LPS and then infected with γHV-68, only a small percentage of cells was productively infected. However, limiting-dilution assays to measure viral reactivation demonstrated that the mature DCs were latently infected with γHV-68. Electron microscopy revealed the presence of capsids in the nucleus of immature DCs but not in mature DCs. Interestingly, infection of immature DCs by γHV-68 did not result in upregulation of the co-stimulatory molecules CD80 and CD86 or MHC class I and II, or induce cell migration, suggesting that the virus infection did not induce DC maturation. Furthermore, γHV-68 infection of immature DCs did not result in elevated interleukin-12, an important cytokine in the induction of T-cell responses. Finally, lipopolysaccharide and poly(I : C) stimulation of γHV-68-infected immature DCs did not induce increases in the expression of co-stimulatory molecules and MHC class I or II compared with mock-treated cells, suggesting that γHV-68 infection blocked maturation. Taken together, these data demonstrate that γHV-68 infection of DCs differs depending on the maturation state of the DC. Moreover, the block in DC maturation suggests a possible immunoevasion strategy by γHV-68.

scholarly journals Dendritic Cells Loaded with Tumor B Cells Elicit Broad Immunity against Murine Gammaherpesvirus 68 but Fail To Prevent Long-Term Latency

2010 ◽  
Vol 84 (17) ◽  
pp. 8975-8979
Author(s):  
Janet Weslow-Schmidt ◽  
Fang Ye ◽  
Stephanie S. Cush ◽  
Kathleen A. Stuller ◽  
Marcia A. Blackman ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
B Cells ◽  
Acute Infection ◽  
Dendritic Cell Vaccination ◽  
Murine Gammaherpesvirus ◽  
Attenuated Viruses ◽  
Gammaherpesvirus 68 ◽  
Vaccine Approach ◽  
Murine Gammaherpesvirus 68

ABSTRACT It is still unknown whether a noninfectious gammaherpesvirus vaccine is able to prevent or reduce virus persistence. This led us to use dendritic cells loaded with tumor B cells as a vaccine approach for the murine gammaherpesvirus 68 (γHV68) model of infection. Dendritic cells loaded with UV-irradiated latently infected tumor B cells induce broad, strong, and long-lasting immunity against γHV68. Dendritic cell vaccination prevents the enlargement of lymph nodes and severely limits acute infection and early latency but does not prevent γHV68 from establishing long-term latency. Our findings support the concept that attenuated viruses may be the best vaccine option for preventing gammaherpesvirus persistence.

Adenosine affects expression of membrane molecules, cytokine and chemokine release, and the T-cell stimulatory capacity of human dendritic cells

Blood ◽  
2003 ◽  
Vol 101 (10) ◽  
pp. 3985-3990 ◽  
Author(s):  
Elisabeth Panther ◽  
Silvia Corinti ◽  
Marco Idzko ◽  
Yared Herouy ◽  
Matthias Napp ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Mhc Class I ◽  
Class I ◽  
Interleukin 12 ◽  
T Helper 1 ◽  
Membrane Expression ◽  
Hla Dr ◽  
Factor Α ◽  
Human Dendritic Cells ◽  
Th1 Immune Responses

Abstract Dendritic cells (DCs) express functional purinergic type 1 receptors, but the effects of adenosine in these antigen-presenting cells have been only marginally investigated. Here, we further characterized the biologic activity of adenosine in immature DCs (iDCs) and lipopolysaccharide (LPS)–matured DCs (mDCs). Chronic stimulation with adenosine enhanced the macropinocytotic activity and the membrane expression of CD80, CD86, major histocompatibility complex (MHC) class I, and HLA-DR molecules on iDCs. Adenosine also increased LPS-induced CD54, CD80, MHC class I, and HLA-DR molecule expression in mDCs. In addition, adenosine dose-dependently inhibited tumor necrosis factor α and interleukin-12 (IL-12) release, whereas it enhanced the secretion of IL-10 from mDCs. The use of selective receptor agonists revealed that the modulation of the cytokine and cell-surface marker profile was due to activation of A2 adenosine receptor. Functionally, adenosine reduced the allostimulatory capacity of iDCs, but not of mDCs. More important, DCs matured in the presence of adenosine had a reduced capacity to induce T helper 1 (Th1) polarization of naive CD4+ T lymphocytes. Finally, adenosine augmented the release of the chemokine CCL17 and inhibited CXCL10 production by mDCs. In aggregate, the results provide initial evidence that adenosine diminishes the capacity of DCs to initiate and amplify Th1 immune responses.

scholarly journals CD80 and CD86 Control Antiviral CD8+ T-Cell Function and Immune Surveillance of Murine Gammaherpesvirus 68

2006 ◽  
Vol 80 (18) ◽  
pp. 9159-9170 ◽  
Author(s):  
Shinichiro Fuse ◽  
Joshua J. Obar ◽  
Sarah Bellfy ◽  
Erica K. Leung ◽  
Weijun Zhang ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Immune Responses ◽  
Neutralizing Antibodies ◽  
Immune Surveillance ◽  
Viral Reactivation ◽  
Classical Pathway ◽  
Murine Gammaherpesvirus ◽  
Gammaherpesvirus 68 ◽  
Murine Gammaherpesvirus 68

ABSTRACT The interactions between CD80 and CD86 on antigen-presenting cells and CD28 on T cells serve as an important costimulatory signal in the activation of T cells. Although the simplistic two-signal hypothesis has been challenged in recent years by the identification of different costimulators, this classical pathway has been shown to significantly impact antiviral humoral and cellular immune responses. How the CD80/CD86-CD28 pathway affects the control of chronic or latent infections has been less well characterized. In this study, we investigated its role in antiviral immune responses against murine gammaherpesvirus 68 (MHV-68) and immune surveillance using CD80/CD86−/− mice. In the absence of CD80/CD86, primary antiviral CD8+ T-cell responses and the induction of neutralizing antibodies were severely impaired. During long-term immune surveillance, the virus-specific CD8+ T cells were impaired in IFN-γ production and secondary expansion and exhibited an altered phenotype. Surprisingly, a low level of viral reactivation in the lung was observed, and this effect was independent of CD28 and CTLA-4. Thus, CD80 and CD86, signaling through CD28 and possibly another unidentified receptor, are required for optimal immune surveillance and antiviral immune responses to murine gammaherpesvirus.

scholarly journals Identification of cis Sequences Required for Lytic DNA Replication and Packaging of Murine Gammaherpesvirus 68

2004 ◽  
Vol 78 (17) ◽  
pp. 9123-9131 ◽  
Author(s):  
Hongyu Deng ◽  
Julia T. Chu ◽  
No-Hee Park ◽  
Ren Sun
Keyword(s):  
Dna Replication ◽  
Gene Delivery ◽  
Viral Genome ◽  
De Novo ◽  
Lytic Replication ◽  
Viral Reactivation ◽  
Murine Gammaherpesvirus ◽  
Gene Delivery Vectors ◽  
Gammaherpesvirus 68 ◽  
Murine Gammaherpesvirus 68

ABSTRACT Human gammaherpesviruses are associated with lymphomas and other malignancies. Murine gammaherpesvirus 68 (MHV-68) infection of mice has emerged as a model for understanding gammaherpesvirus pathogenesis in vivo. In contrast to human gammaherpesviruses, MHV-68 replicates in permissive cell lines in a robust manner, presenting an efficient model to study the basic mechanisms for DNA replication and recombination processes. In addition, MHV-68 also infects a broad range of cells of different tissue types and from different host species, and the viral genome persists as an episome in infected cells. These features make MHV-68 an attractive system on which to build gene delivery vectors. We have therefore undertaken a study to identify the cis elements required for MHV-68 genome replication and packaging. Here we report that an 8.4-kb MHV-68 genomic fragment between ORF66 and ORF73 conferred on the plasmid the ability to replicate; replication required the presence of either de novo viral infection or viral reactivation from latency. We further mapped the origin of lytic replication (oriLyt) to a 1.25-kb region. Moreover, we demonstrated that the terminal repeat of the viral genome is sufficient for packaging of the replicated oriLyt plasmid into mature viral particles. Functional identification of the MHV-68 oriLyt and packaging signal has laid a foundation for investigating the mechanisms controlling gammaherpesvirus DNA replication during the viral lytic phase and will also serve as a base on which to design gene delivery vectors.

scholarly journals Murine Gammaherpesvirus-68 Inhibits Antigen Presentation by Dendritic Cells

PLoS ONE ◽  
2007 ◽  
Vol 2 (10) ◽  
pp. e1048 ◽  
Author(s):  
Christopher M. Smith ◽  
Michael B. Gill ◽  
Janet S. May ◽  
Philip G. Stevenson
Keyword(s):  
Dendritic Cells ◽  
Antigen Presentation ◽  
Murine Gammaherpesvirus ◽  
Gammaherpesvirus 68 ◽  
Murine Gammaherpesvirus 68

scholarly journals CD40 Engagement on Dendritic Cells, but Not on B or T Cells, Is Required for Long-Term Control of Murine Gammaherpesvirus 68

2008 ◽  
Vol 82 (22) ◽  
pp. 11016-11022 ◽  
Author(s):  
Francesca Giannoni ◽  
Ashley Shea ◽  
Chandra Inglis ◽  
Lian Ni Lee ◽  
Sally R. Sarawar
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd4 T Cells ◽  
Viral Reactivation ◽  
Cd4 T Cell ◽  
Murine Gammaherpesvirus ◽  
Cd40 Expression ◽  
Gammaherpesvirus 68 ◽  
Murine Gammaherpesvirus 68

ABSTRACT CD4 T cells are not essential for primary clearance of replicating murine gammaherpesvirus 68 (MHV-68) but are required for effective long-term control. The virus reactivates in the lungs of major histocompatibility complex class II-deficient (CII−/−) mice that lack functional CD4 T cells. CD40 ligand (CD40L) is upregulated on activated CD4 T cells, and it is thought that CD40-CD40L interactions are an important component of CD4 T-cell help. Our previous studies have shown that agonistic antibodies to CD40 can substitute for CD4 T-cell function in the long-term control of MHV-68. In the present study, we sought to identify the CD40-positive cell type mediating this effect. To address this question, we adoptively transferred MHV-68 peptide-pulsed CII−/− dendritic cells (DC) that had been treated with an agonistic antibody to CD40 into MHV-68-infected CII−/− recipients. Viral reactivation was significantly lower in mice injected with anti-CD40-treated DC than in those injected with control DC or in mice that did not receive any DC. However, in similar experiments with B cells, anti-CD40 treatment had no effect. We also investigated the requirement for CD40 expression on T cells by adoptive transfer of T cells from CD40+/+ or CD40−/− mice into T-cell-deficient recipients that were subsequently infected with MHV-68. The results showed that CD40 expression on T cells is not necessary for preventing viral reactivation. Taken together, our data suggest that CD40 engagement on DC, but not on T or B cells, is essential for effective long-term control of MHV-68.

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