Orf virus-encoded interleukin-10 inhibits maturation, antigen presentation and migration of murine dendritic cells

Abstract

Orf virus (ORFV) belongs to the genus Parapoxvirus and induces cutaneous pustular lesions in sheep, goats and humans. ORFV is unusual in that it has the ability to reinfect its host and this suggests that the generation of immunological memory has been impaired, thus exposing the host to subsequent infection. The discovery that ORFV encodes an IL-10-like virokine raises the question of whether this factor adversely affects the cells that initiate the acquired immune response. We examined the effect of ORFV-IL-10 on immature murine bone marrow-derived dendritic cells (BMDC). Immature BMDC are activated on exposure to antigen and undergo maturation. This process is characterized by increased expression of CD80, CD86 and MHC class II and reduced antigen uptake. We found that the maturation of BMDC is impaired in cells treated with ORFV-IL-10 prior to antigen exposure and this was exemplified by the reduced expression of the cell-surface markers described above. We have also shown that the activation of a haemagglutinin peptide (HAT)-specific T cell hybridoma by dendritic cell-mediated presentation of HAT and heat-inactivated influenza virus AP8/34 was markedly reduced following exposure to ORFV-IL-10. Finally, we examined the effect of ORFV-IL-10 on Langerhans' cell (LC) migration using cultured murine skin explant tissue and showed that this virokine impaired the spontaneous migration of LC from the epidermis and induced changes in LC morphology. Our findings suggest that ORFV-IL-10 has the capacity to impair the initiation of an acquired immune response and hence inhibit the generation of immunological memory necessary for immunity on subsequent exposure. INTRODUCTIONThe initiation of an acquired immune response to a virus requires that antigen be taken up by dendritic cells (DC) in the periphery, processed and transported to the draining lymphoid tissue to be presented to T cells (reviewed in Palucka & Banchereau, 2002). For this sequence of events to occur, DC must first become activated by signals transmitted through the interaction of viral products with pattern recognition receptors expressed on the surface of these cells. DC form the vital bridge between the innate response and the acquired response. In doing so they become an attractive target for virally mediated immunosuppression.Viruses evade the immune response of the host by an array of mechanisms including the production of cytokine homologues capable of deflecting, down regulating or aborting cell-mediated immunity (Alcami & Koszinowski, 2000).Interleukin (IL)-10 homologues are produced by EpsteinBarr virus (EBV) (Moore et al., 1990), equine herpesvirus (EHV) (Rode et al., 1993), cytomegalovirus (Kotenko et al., 2000, Yaba-like disease virus (Lee et al., 2001) and orf virus (ORFV) (Fleming et al., 1997). Mammalian IL-10, a prototypic anti-inflammatory cytokine, is capable of both immunosupressive and immunostimulatory functions (reviewed in Fickenscher et al., 2002). This cytokine is known to inhibit DC function and ultimately the induction of ant...

The role of interleukin 10 in the pathogenesis and potential treatment of skin diseases

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Modulation of macrophage functions by sheeppox virus provides clues to understand interaction of the virus with host immune system

“…Poxviruses modulate the immune response in infected hosts by inhibiting the synthesis and release of IL-1 from infected cells; encoding soluble cytokine receptors for tumor TNF-α, TNF-β, IL-1, and importantly, IFN-γ; synthesizing virus-encoded cytokines like epidermal growth factor and transforming growth factor, which antagonize the effects of host cytokines mediating the antiviral process [16,26]. In addition, inducing apoptosis in a significant number of antigen-presenting cells [20] as well as inducing IL-10 release that has the capacity to impair the initiation of an acquired immune response [16,21]. If the viruses fail to secrete such immunomodulating proteins, as when the respective genes are deleted or the viruses are inactivated, the strong immunogenicity of the viruses may induce host immune reactions which are no longer inhibited [19].…”

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