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-1beta (IL-1beta),
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 DeltaE3L virus, but not wild-type vaccinia virus, triggered proteolytic decay of
IkappaBalpha. These results suggest a novel role for the E3L
protein as an antagonist of the
NF-kappaB signaling pathway. DeltaE3L-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. DeltaK1L-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.