HCMV infection of PDCs deviates the NK cell response into cytokine-producing cells unable to perform cytotoxicity

Plasmacytoid dendritic cells (PDCs) are thought to induce natural killer (NK) cell CD69 expression, cytotoxicity, and cytokine secretion. Since human cytomegalovirus (HCMV) interferes with multiple functions of infected cells, we investigated whether the HCMV infection of PDCs affects NK cell activation. Human PDCs infected with HCMV strain VR1814 at multiplicity of infection (MOI) 10 or stimulated with control CpG-A were cocultured with human NK cells in an autologous system. As expected, CpG-stimulation of PDCs increased expression of the NK cell activation marker CD69, enhanced cytotoxicity and stimulated secretion of tumor necrosis factor (TNF)-alpha and IFN-alpha, but not IFN-gamma, and induced NK cell migration. In contrast, incubation with HCMV-infected PDCs induced CD69 expression, migration and elevated production of both TNF-alpha and IFN-gamma by NK cells, but these cells did not exhibit enhanced cytotoxicity. Also, HCMV-infected PDCs were unable to induce increased intracellular perforin levels. Thus, HCMV infection of PDCs induce NK cells to increase CD69 expression and produce inflammatory cytokines, but infected PDCs are unable to induce NK cell cytotoxicity. This NK cell phenotype with impaired killing abilities, but enhanced production of inflammatory cytokines may instead facilitate reactivation and replication of HCMV. This data indicate that HCMV can target PDCs through novel dual strategies that may result in evasion of the innate immune response at the same time as facilitating virus reactivation and replication early in the infection, through enhanced inflammation.