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Journal of Virology, October 2006, p. 9977-9987, Vol. 80, No. 20
0022-538X/06/$08.00+0     doi:10.1128/JVI.00354-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Vaccinia Virus Infection Attenuates Innate Immune Responses and Antigen Presentation by Epidermal Dendritic Cells

Liang Deng,1 Peihong Dai,2 Wanhong Ding,3 Richard D. Granstein,3 and Stewart Shuman2*

Dermatology Service, Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York 10021,1 Molecular Biology Program, Sloan-Kettering Institute, New York, New York 10021,2 Department of Dermatology, Weill Medical College of Cornell University, New York, New York 100213

Received 20 February 2006/ Accepted 5 July 2006

Langerhans cells (LCs) are antigen-presenting cells in the skin that play sentinel roles in host immune defense by secreting proinflammatory molecules and activating T cells. Here we studied the interaction of vaccinia virus with XS52 cells, a murine epidermis-derived dendritic cell line that serves as a surrogate model for LCs. We found that vaccinia virus productively infects XS52 cells, yet this infection displays an atypical response to anti-poxvirus agents. Whereas adenosine N1-oxide blocked virus production and viral protein synthesis during a synchronous infection, cytosine arabinoside had no effect at concentrations sufficient to prevent virus replication in BSC40 monkey kidney cells. Vaccinia virus infection of XS52 cells not only failed to elicit the production of various cytokines, including tumor necrosis factor alpha (TNF-{alpha}), interleukin-1ß (IL-1ß), IL-6, IL-10, IL-12 p40, alpha interferon (IFN-{alpha}), and IFN-{gamma}, it actively inhibited the production of proinflammatory cytokines TNF-{alpha} and IL-6 by XS52 cells in response to exogenous lipopolysaccharide (LPS) or poly(I:C). Infection with a vaccinia virus mutant lacking the E3L gene resulted in TNF-{alpha} secretion in the absence of applied stimuli. Infection of XS52 cells or BSC40 cells with the {Delta}E3L virus, but not wild-type vaccinia virus, triggered proteolytic decay of I{kappa}B{alpha}. These results suggest a novel role for the E3L protein as an antagonist of the NF-{kappa}B signaling pathway. {Delta}E3L-infected XS52 cells secreted higher levels of TNF-{alpha} and IL-6 in response to LPS and poly(I:C) than did cells infected with the wild-type virus. XS52 cells were productively infected by a vaccinia virus mutant lacking the K1L gene. {Delta}K1L-infected cells secreted higher levels of TNF-{alpha} and IL-6 in response to LPS than wild-type virus-infected cells. Vaccinia virus infection of primary LCs harvested from mouse epidermis was nonpermissive, although a viral reporter protein was expressed in the infected LCs. Vaccinia virus infection of primary LCs strongly inhibited their capacity for antigen-specific activation of T cells. Our results highlight suppression of the skin immune response as a feature of orthopoxvirus infection.

* Corresponding author. Mailing address: Molecular Biology Program, Sloan-Kettering Institute, 1275 York Ave., New York, NY 10021. Phone: (212) 639-7145. Fax: (212) 717-3623. E-mail: s-shuman{at}ski.mskcc.org.

Journal of Virology, October 2006, p. 9977-9987, Vol. 80, No. 20
0022-538X/06/$08.00+0     doi:10.1128/JVI.00354-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



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