Interference of Varicella-Zoster Virus (VZV) with the CD1 antigen presenting system on immature dendritic cells

Varicella-zoster virus (VZV) which belongs to the family of herpesviruses is restricted to humans and distributed worldwide. The seroprevalence is over 95%. Primary infection of VZV causes chickenpox, a typical childhood disease characterized by fever and disseminated rash. Thereafter, VZV establishes a lifelong latency within sensory ganglia and can be reactivated to cause herpes zoster. This disease is characterized by lesions confined mostly to a single dermatome. A frequent complication of herpes zoster is the painful postherpetic neuralgia. Since 1995 the attenuated strain V-Oka of VZV is successfully used as vaccine in the United States of America to immunize children against VZV infection. In 2004 the vaccine was also licensed for Germany. In contrast to infection by circulating virulent VZV strains, vaccination with V-Oka remains asymptomatic. T cell mediated immunity is important to resolve VZV infection and an age related decline in VZV specific T cell mediated immunity is correlated with an increase of the incidence for herpes zoster and postherpetic neuralgia. The skin is the major replication site of VZV and immunological differences between virulent VZV and the vaccine should become most apparent within this immune organ. However, these differences have not been elucidated so far. Cutaneous immune cells comprising epidermal Langerhans cells (LCs), dermal dendritic cells (DDCs), inflammatory den-dritic cells and intraepithelial γδ T cells contribute to the induction of effective antiviral immune responses. Thus, the major focus of this study was to highlight cutaneous immune responses to virulent VZV strains as compared to the vaccine. Therefore, clinical isolates of circulating VZV genotypes in Europe were included in this study. In this study the disappearance of LCs in skin lesions of herpes zoster patients was observed. In contrast, a strong infiltration of myeloid-derived inflammatory DCs has been detected. Furthermore, it has been shown for the first time that ex vivo isolated LCs and DDCs were permissive for VZV infection. Most importantly, no differences between the effects of the vaccine strain V-Oka and a virulent VZV strain have been observed. In vitro studies with monocyte-derived dendritic cells (DCs), reflecting inflammatory DCs, showed that they were efficiently infected by both, the vaccine and a virulent VZV strain. Intriguingly , a significant upregulation of CD1c molecules on VZV-infected DCs was observed. Func-5 tional investigations using intraepithelial CD1c-restricted γδ T cells revealed that DCs infected with the vaccine virus were fully instructed to mature, thereby promoting IFN-γ secretion of γδ T cells. …