title: Vaccinia virus induces strong immunoregulatory cytokine production in healthy human epidermal keratinocytes: a novel strategy for immune evasion.
abstract: Iatrogenic cutaneous infection with vaccinia virus (VV) and naturally occurring systemic infection with variola virus both lead to the characteristic skin "pox" lesions. Despite significant medical experience with both viruses, surprisingly little is understood about the interactions between these poxviruses and healthy resident skin cells. In recent years, it has become clear that skin plays an essential role in modulating both innate and adaptive immune responses, in part by producing and responding to a variety of cytokines and chemokines upon stimulation. Antagonists of many of these compounds are encoded in poxvirus genomes. Infection of skin cells with poxvirus may lead to a unique pattern of cytokine and chemokine production that might alter the cutaneous immune surveillance function. In this study, we infected primary cultures of human skin cells with VV and monitored antigen expression, virus replication, and cytokine production from the infected cells. While T cells, Langerhans cells, and dermal dendritic cells were infected abortively, keratinocytes, dermal fibroblasts, and dermal microvascular endothelial cells (HMVEC-d) all supported the complete virus life cycle. In contrast to the robust viral replication in fibroblasts and HMVEC-d, only limited viral replication was observed in keratinocytes. Importantly, VV infection of keratinocytes led to up-regulation of immunoregulatory and Th2 cytokines, including transforming growth factor beta, interleukin-10 (IL-10), and IL-13. We propose that the rapid induction of keratinocyte Th2 and immunoregulatory cytokines represents a poxvirus strategy to evade immune surveillance, and the limited viral multiplication in keratinocytes may be a protective mechanism to help the immune system "win the race."
authors.affiliation: Harvard Skin Disease Research Center, Department of Dermatology, Brigham and Women's Hospital, 77 Avenue Louis Pasteur, Suite 672, Boston, MA 02115, USA.
authors.forename: Luzheng
authors.initials: L
authors.lastname: Liu
authors.forename: Zhan
authors.initials: Z
authors.lastname: Xu
authors.forename: Robert C
authors.initials: RC
authors.lastname: Fuhlbrigge
authors.forename: Victor
authors.initials: V
authors.lastname: Peña-Cruz
authors.forename: Judy
authors.initials: J
authors.lastname: Lieberman
authors.forename: Thomas S
authors.initials: TS
authors.lastname: Kupper
mesh_terms: D016207:Cytokines / Q000096:biosynthesis*; D004730:Endothelium, Vascular / Q000166:cytology / Q000276:immunology / Q000821:virology; D000078404:Epidermal Cells; D004817:Epidermis / Q000276:immunology / Q000821:virology*; D005347:Fibroblasts / Q000276:immunology / Q000821:virology; D006801:Humans; D007121:Immunocompetence; D015603:Keratinocytes / Q000276:immunology / Q000821:virology*; D008833:Microcirculation; D018418:Th2 Cells / Q000276:immunology*; D015854:Up-Regulation; D014616:Vaccinia virus / Q000276:immunology / Q000472:pathogenicity*; D014779:Virus Replication
chemical_list: D016207:Cytokines