Of note, the IFN-a treatment administered to the Klra8 mice did not significantly change the level of viral replication in these animals. Very low but detectable levels of infectious viral particles were observed in both control-treated and IFN-a-injected Klra8 mice (1.9460.35 versus 1.9260.11 log pfu/spleen), which contrasted sharply with the high viral replication observed in BALB/c animals (5.260.04 log pfu/ spleen). These results demonstrate that exogenous injection of IFN-a in Klra8 mice is sufficient to decrease the numbers of cDCs and to ablate early antiviral CD8 T cell responses, and, therefore, that excessive levels of IFN-a can have a direct negative impact on antiviral immune cell responses in a manner that is independent of the level of viral replication in the host. The possibility remains that other innate cytokines, such as IL-12 and TNF-a, which are produced at much higher levels in BALB/c as compared to Klra8 mice, may also bear some contribution to this function, in a synergistic or redundant manner with IFN-a/b. In any case, our data strongly suggest that the ability of Klra8 mice to preserve an intact cDC compartment and to mount early CD8 T cell responses is in part due to their ability to control viral replication very early without the need for the host to produce high systemic levels of IFN-a/b. Altogether, our data thus identify how naturally occurring differences in the interactions between a virus and its host can tilt the balance between the various functions of IFN-a/b, and eventually other innate cytokines, towards conditions promoting the induction of early adaptive immunity, rather than the development of a state of transient immunosuppression.