Infection of Dendritic Cells by a γ2-Herpesvirus Induces Functional Modulation

Abstract

The murine γ-herpesvirus-68 (γHV68) establishes viral latency in dendritic cells (DCs). In the present study, we examined the specific consequences of DC infection by γHV68, both in vivo and in vitro. Ex vivo analysis of infected mice showed that the virus colonizes respiratory DCs very early after infection and that all subsets of splenic DCs analyzed are viral targets. We have developed and characterized an in vitro model of γHV68 infection of DCs. Using this model, we demonstrated that viral infection neither induces full DC maturation nor interferes with exogenous activation, which is assessed by cell surface phenotypic changes. However, whereas γHV68 infection alone failed to elicit cytokine secretion, IL-10 secretion of exogenously activated DCs was enhanced. Furthermore, γHV68-infected DCs efficiently stimulated virus-specific T cell hybridomas but failed to induce alloreactive stimulation of normal T cells. These data indicate that viral infection doesn’t interfere with Ag processing and presentation but does interfere with the ability of DCs to activate T cells. The inhibition of T cell activation was partially reversed by blocking IL-10. Analysis of infected mice shows elevated levels of IL-10 expression in DCs and that lack of endogenous IL-10 is associated with decreased γHV68 long-term latency. Taken together, these observations indicate that γ2-herpesvirus infection of DCs is a mechanism of viral immune evasion, partially mediated by IL-10.

Murine gammaherpesvirus 68 infection protects lupus-prone mice from the development of autoimmunity

“…The virus may otherwise alter the development of autoimmunity by modulating DCs, which are known to contribute to the development of lupus in B6.Sle123 mice by producing large amounts of proinflammatory cytokines and driving high levels of B-cell and T-cell proliferation (68)(69)(70). Acute infection of DCs with γHV68 decreases their ability to present antigen and to express proinflammatory cytokines (20,21,29,61,71). Reduced endocytic function of DCs during γHV68 acute infection was also observed in the context of the autoimmune NOD genetic background (29).…”

“…injection or intranasal administration of virus particles results in a productive acute infection that manifests with enhanced Ig secretion, lymphoproliferation, and cytokine production resembling the mononucleosis that follows EBV infection in almost half of infected adult human beings (10)(11)(12)(13). Similar to the time course of EBV infection in humans, the mouse immune system controls the γHV68 virus within 2 to 3 wk after the initial infection (13)(14)(15), and the virus goes latent in B cells, macrophages, dendritic cells (DCs), and epithelial cells (16)(17)(18)(19)(20)(21). This chronic infection persists for the rest of the individual's life.…”

A Replication-Deficient Murine γ-Herpesvirus Blocked in Late Viral Gene Expression Can Establish Latency and Elicit Protective Cellular Immunity

“…The frequency of latently infected cells capable of spontaneous in vitro reactivation was assessed using an infective center assay, as previously described (25). Ten-fold serial dilutions (in triplicate) of splenocytes starting at 10 6 cells/well, were plated onto monolayers of NIH-3T3 mouse fibroblast cells.…”

Interference with Dendritic Cell Populations Limits Early Antigen Presentation in Chronic γ-Herpesvirus-68 Infection

“…Earlier work has suggested that MK3 was not active in DCs during infection (23). More recent evidence showed that MK3 can operate in DCs, at least in vitro (24), but it is less clear that it is active in vivo.…”

“…Most of our understanding of the function of MK3 is derived from in vitro studies (23,24). In this setting, lytically infected DCs downregulated CD86 and MHC class I expression, resulting in poor Ag presentation to CD8 + T cells (24).…”