In vivo during MCMV infection, pDC activation for innate cytokine production increases with the doses of viral inoculum used for the infection of a given mouse strain [116] . pDC cytokine responses to MCMV infection also increase dramatically in mice unable of efficient innate control of viral replication early after challenge, as a consequence of a selective impairment in antiviral NK cell activity, due either to antibody-dependent depletion of these cells or to the absence of the gene encoding the NK cell activation receptor specific for infected cells [116] . Reciprocally, early treatment of infected mice with an antiviral drug leads to a dramatic decrease of pDC cytokine production. Therefore, although innate cytokine production during MCMV infection is independent of endogenous viral replication in pDCs, it is tuned accordingly to the global level of viral replication in the host. Thus, rather than being the primary mechanism of defense against viral infections, high systemic production of IFN-I and other innate cytokines by spleen pDCs may represent a fail-safe mechanism. It may be turned on to maximal levels, at the risk of immunopathology, only in the case of high systemic viral replication associated to high levels of circulating ligands for TLR7 or TLR9, when other innate immune mechanisms have failed to efficiently control the virus. This hypothesis is supported by studies of airway infections of mice with viruses that do not belong to herpesviridae. For example, intranasal challenge with NDV leads to pDC production of IFN-I (in the spleen, specifically) only when the first line of defense made by alveolar macrophages is experimentally disrupted and the infection has spread systemically [47] .