4.6 Article

Interplay between Modified Vaccinia Virus Ankara and Dendritic Cells: Phenotypic and Functional Maturation of Bystander Dendritic Cells

Journal

JOURNAL OF VIROLOGY
Volume 85, Issue 11, Pages 5532-5545

Publisher

AMER SOC MICROBIOLOGY
DOI: 10.1128/JVI.02267-10

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Funding

  1. Argentinean Agency for the Promotion of Science and Technology (ANPCyT) [34410]
  2. Argentinean National Research Council (CONICET)
  3. Fogarty AIDS International Training and Research Program
  4. Spain Agency for International Cooperation for Development [A/025293/09]
  5. National Center for Research Resources [P51 RR013986, R24 RR023345]
  6. Deutsche Forschungsgemeinschaft [SFB456 TP B7]

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Modified vaccinia virus Ankara (MVA) is an attenuated poxvirus strain, currently under evaluation as a vaccine vector in various clinical settings. It has been reported that human dendritic cells (DCs) mature after infection with MVA, but reports on the functionality of DCs have so far been controversial. In this work, we studied the phenotype and functionality of MVA-infected DCs. As previously reported, we found that human monocyte-derived DCs upregulated CD86 and HLA-DR in response to MVA infection. Moreover, infected DCs produced a broad array of chemokines and cytokines and were able to activate and induce gamma interferon (IFN-gamma) production both in CD4(+) and in CD8(+) allogeneic T cells and in specific autologous peripheral blood lymphocytes (PBLs). Analysis of DC maturation following infection with a recombinant green fluorescent protein (GFP)-expressing MVA revealed that upregulation of CD86 expression was mainly observed in GFP(neg) (bystander) cells. While GFP(pos) (infected) DCs produced tumor necrosis factor alpha (TNF-alpha), they were unable to produce CXCL10 and were less efficient at inducing IFN-gamma production in CEF-specific autologous PBLs. Maturation of bystander DCs could be achieved by incubation with supernatant from infected cultures or with apoptotic infected cells. Type I IFNs were partially responsible for the induction of CXCL10 on bystander DCs. Our findings demonstrate for the first time that, in MVA-infected DC cultures, the leading role with respect to functionality and maturation characteristics is achieved by the bystander DCs.

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