Characterization of cytokine/chemokine networks promoting localized recruitment of immune effector cells for antiviral defense

Effective delivery of innate and adaptive immune mechanisms depends on the recruitment of effector cells to sites of infection. Our laboratory has identified a cytokine and chemokine cascade that is induced upon infection with MCMV and plays a critical role in inflammation and the balance between life and death. It has been shown that IFN-alpha/beta-mediated effects promote the production of MIP-1alpha by mediating the recruitment of MIP-1alpha-producing macrophages to liver during MCMV infection. This results in NK cell inflammation and delivery of localized IFN-gamma in order to support antiviral defense at this site. However, it remains to be determined if IFN-alpha/beta induces an intermediary chemokine directly required for macrophage recruitment. Herein, I demonstrate that IFN-alpha/beta effects promote MCP-1 expression by resident liver cells. Additionally, I show that MCP-1/CCR2 interactions are required for recruitment of macrophages, NK cells and promotion of MIP-1alpha and IFN-gamma expression in liver, leading to viral clearance and survival. I also investigated mechanisms promoting IFN-alpha/beta production in liver during MCMV. Here, I demonstrate that plasmacytoid dendritic cells are major contributors to IFN-alpha/beta production and that IFN-alpha/beta expression and hepatic viral clearance is dependent upon the presence of MyD88 but not TLR9. Finally, we investigated the requirements for T cell recruitment to liver following infection. At time points corresponding with T cell accumulation, we observed protein expression of both Mig and IP-10, two potent T cell chemoattractants. Neutralization of these chemokines as well as studies using CXCR3-deficient animals, revealed a function for these chemokines in mediating T cell recruitment and promoting antiviral defense. In addition, CCR2 was also identified as a key player in directing T cell trafficking to liver, but these effects were not mediated by MCP-1. Taken together, these studies contribute to our understanding of in vivo chemokine biology and function by defining cytokine and chemokine networks and the mechanisms promoting their expression. Collectively, these effects are required for effective antiviral defense in tissues.