Too much of a good thing: Sustained type 1 interferon signaling limits humoral responses to secondary viral infection.

The induction of a pan-immunosuppressive state is a central feature of persistent viral infections. Over the past decade, multiple pathways have been identified that contribute to immune suppression. Recently, it was revealed that aberrant or sustained type 1 interferon (IFN-I) production or signaling is a central contributor to immune suppression elicited during persistent viral infection. In this issue, Honke et al. [Eur. J. Immunol. 2016. 46: 372-380] identify that IFN-I signaling promotes an immune suppressive state during persistent lymphocytic choriomeningitis virus infection by inhibiting enforced virus replication in CD169(+) macrophages. The authors demonstrate that mice infected with a persistent strain of lymphocytic choriomeningitis virus have blunted humoral immune responses to a superinfecting vesicular stomatitis virus infection. The absence of virus replication in CD169(+) macrophages was not due to antiviral CD8(+) T cell-mediated killing of CD169(+) macrophages, but required sustained IFN-I responses. In turn, reduction in vesicular stomatitis virus replication in CD169(+) macrophages resulted in a reduction in antigen production, which is necessary for generating optimal humoral responses. This study highlights a novel mechanism by which IFN-I signaling promotes an immune suppressive state during persistent viral infection.