To further link the early viral load and the level of IFN-a/b production by pDCs, we performed infections of BALB/c and Klra8 mice with 5-fold serial dilutions of viral inoculums, leading to challenge doses from 10 3 to 1.25 3 10 5 pfu/mouse. Systemic IFN-a titers in these animals were measured by (B) Splenic leukocytes were isolated from Klra8 and BALB/c mice and analyzed for the frequency of IFN-a/b þ pDCs and IL-12 þ pDCs directly ex vivo. Numbers in dot plots represent the percent of IFN-a/b þ and percent of IL-12 þ cells within the total pDC population. One representative animal from groups of three mice for day 1.5 post-MCMV infection is shown. Graphs represent the total numbers of IFN-a/b þ pDCs and IL-12 þ pDCs present in the spleens of Klra8 and BALB/c mice on days 0, 1.5, 2, and 3 post-MCMV infection. Results are expressed as mean 6 SD of three mice per group and in ten thousands of cells. One experiment representative of three for (A, B) is shown. *p 0.05; **p 0.01; § ¼ not detected. doi:10.1371/journal.ppat.0030123.g001 ELISA on serum samples, and the numbers of pDCs producing IFN-a/b by flow cytometry ( Figure S2 ). The results clearly showed that the amount of IFN-a/b secreted by pDCs increases dramatically at high viral dose inoculums in Klra8 mice to levels similar to those observed in BALB/c animals. A 5-fold difference in the virus inoculums from 5 3 10 3 to 2.5 3 10 4 pfu/mouse is sufficient to switch on IFN-a/b production by pDCs in Klra8 mice from very low levels to nearly maximal levels similar to those observed in BALB/c animals. At low dose viral infection (10 3 pfu/mouse), BALB/c mice are still activated for nearly maximal pDC cytokine production. Thus, BALB/c and Klra8 animals are confirmed to exhibit dramatically different levels of pDC IFN-a/b production over more than a 10-fold range of viral inoculums. These data also show that the pDCs of Klra8 mice are able to produce high levels of IFN-a/b under conditions of stimulation with high viral inoculums. Moreover, NK cell depletion in Klra8 mice infected with low virus inoculums was also shown to lead to a dramatic increase in pDC IFN-a/b production, almost to the levels observed in BALB/c animals ( Figure S2 ). Altogether, these data thus show that the ability of the host to control MCMV replication early through NK cell responses limits the activation of pDCs and therefore prevents the induction of very high systemic levels of IFN-a/b and IL-12. These data also demonstrate that the pDCs of Klra8 mice are not intrinsically deficient for IFN-a/b production in response to MCMV infection.