Using MCMV as a model, we were the first to report that pDCs are the major producers of IFN-I in vivo during a viral infection [12, 32] . pDCs isolated from the spleen of d1.5 MCMV-infected mice produced high levels of IFN-I ex vivo without any restimulation, while the cytokines could not be detected in the supernatant from cDCs isolated from the same animals [13] . A dramatic decrease in ex vivo IFN-I production was observed in splenocytes depleted of pDCs. Moreover, systemic IFN-I production was dramatically reduced in infected animals upon anti-GR1 [12, 32] or anti-BST2 [39] antibody-mediated pDC depletion. These results thus demonstrated that pDCs are the major producers of systemic IFN-I in vivo during MCMV infection, even though CD11b + cDCs that are infected by MCMV in vitro at a high multiplicity of infection can also produce significant levels of IFN-I [42]. This conclusion was further confirmed by several other complementary approaches. First, pDCs isolated from the spleen of MCMV-infected mice expressed much higher amounts of the mRNA for all the different IFN-α and IFN-β subtypes tested as compared to other splenocytes [43] (Figure 1) . Second, the vast majority of IFN-I expressing cells in vivo in the spleen of infected mice were demonstrated to be pDCs, using intracellular staining with specific antibodies on cell suspensions or tissue sections at 30-36 hours post-infection [43] or YFP-IFNb reporter knockin mice at 12-24 hours post-infection [44] . We showed that splenic pDCs were the major producers of IFN-I in three mouse strains: 129S2, BALB/c and C57BL/6 mice. In all these instances, IFN-I production by splenic pDCs took place relatively rapidly and was very transient since it was easily detectable around 36 hours but not at 24 hours or 44 hours post-infection [43] . Third, a deficient IFN-I production upon MCMV infection was observed in a knockin mouse strain (Ik L/L mice) which harbors a selective block in pDC differentiation at an immature stage in the bone marrow consecutive to a hypomorphic mutation of the IKAROS transcription factor [45] .