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

Abstract

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/sustained type 1 interferon (IFN-I) production/signaling is a central contributor to immune suppression elicited during persistent viral infection. In this issue of Eur. J. Immunol., Honke et al. identify that IFN-I signaling promotes an immune suppressive state during persistent LCMV infection by inhibiting enforced virus replication in CD169⁺ macrophages. The authors demonstrate that mice infected with a persistent Docile strain of Lymphocytic Choriomeningitis virus (LCMV) blunt the humoral adaptive immune response to a superinfecting Vesicular Stomatitis virus (VSV) infection. The absence of virus replication in CD169⁺ macrophages was not due to anti-viral CD8 T cell-mediated killing of CD169⁺ macrophages but required sustained IFN-I responses. In turn, reduction in VSV replication and antigen production in CD169⁺ macrophages reduced 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 and further expands our understanding of how IFN-I signaling promotes an immune suppressive environment.

Persistent viral infections represent a significant public health problem across the globe with hundreds of millions of people currently infected. The induction of a pan-immunosuppressive state is a central feature of many persistent viral infections. Immune suppression induced by persistent viral infections has been shown to occur through multiple mechanism including; the generation of sustained negative immune regulatory molecules (IL-10, PD-1:PD-L1)(1, 2), skewing of the dendritic cell (DC) compartment towards immunosuppressive DCs (3-5), lysis of virally infected stromal cells leading to disorganized lymphoid architecture (6), deletion of antigen specific B cells by anti-viral CD8 T cells(7) and antigen specific T cell depletion by activated natural killer (NK) cells (8, 9). All which contribute to to the immune suppressive state observed. More recently, it was demonstrated that IFN-I signaling promotes immune suppression during persistent virus infection, supporting induction of negative immune regulators (NIR) IL-10 and PD-L1, T cell exhaustion and lymphoid tissue destruction and blockade of IFN-I signaling using an IFN-I receptor-neutralizing antibody reduced immune system activation, decreased expression of NIR, restored lymphoid architecture and CD4 T cell function, leading to hastened viral clearance (10, 11).

In the current issue of European Journal of Immunology Honke, et al. uncover an additional mechanism by which IFN-I signaling can promote immune suppression. Building on their previous findings showing that the induction of an adaptive antibody immune response to VSV relies on enforced replication in CD169+ macrophages through up-regulation of the IFN-I signaling inhibitor, Usp18 (12), they now show that a persistent viral infection impairs the generation of antibodies to vesicular stomatitis virus (VSV), and that this is associated with reduced VSV viral loads in persistently infected hosts (Fig. 1). Mechanistically, inhibition of enforced viral replication in the presence of a persistent virus infection is due to an elevated IFN-I signature within CD169+ macrophages which in turn prevents VSV replication. The authors demonstrate that IFN-I signaling induced by persistent LCMV infection is required to prevent enforced VSV replication using a neutralizing IFNAR1-antibody as well as studies in IRF3/IRF7 double-deficient mice, both which restore the VSV replication in CD169+ macrophages as well as ant-VSV antibody responses. Previous studies demonstrated that lysis of infected cells by virus-specific CD8 T cells promotes LCMV-induced immune suppression however, the authors rule out CD8 T cell involvement by using MHC-I^−/−, perforin^−/− mice as well as neonatal infection with LCMV which results in antigen specific T cell deletion. These results suggest that prolonged production of type I IFN in chronically infected hosts may prevent enforced viral replication of newly infecting viruses, thus markedly limiting the humoral immune responses against secondary viral infections. One surprising finding in the current study is that, during persistent LCMV infection, elevated Usp18 and IFN-I stimulated gene expression is observed in CD169+ macrophages. Given that Usp18 inhibits IFN-I signaling, it will be important to further understand why increases in Usp18 expression do not correlate with a corresponding decrease in IFN-I stimulated gene expression. One possibility is that Usp18 is only effective at curbing IFN-I responsiveness at lower, less sustained IFN-I signaling (similar to what is observed during acute VSV infection). During persistent IFN-I signaling the ability of Usp18 to suppress IFN-I signaling may be lost. Alternatively, it is possible that Usp18 regulates IFN-I responsiveness of CD169⁺ macrophages by an as of yet unidentified mechanism.

Figure 1.

Sustained IFN-I signaling during persistent viral infection limits enforced viral replication during secondary viral infection. (A) VSV infection in naïve animals induces low levels of IFN-I, which allow for virus replication in CD169+ macrophages. This virus replication in turn promotes the generation of viral antigen, priming of antigen-specific B cells, and production of antiviral antibodies to help control infection. (B) During persistent viral infection, sustained IFN-I signaling prevents virus replication in CD169+ macrophages, preventing the generation of viral antigen and induction of antigen-specific B-cell responses and antiviral antibodies. The inhibition of antiviral B-cell responses prevents efficient control of secondary VSV infection.**

Infection with Human Immunodeficiency virus (HIV) is known to result in enhanced susceptibility to multiple co-infecting pathogens over time. Moreover, poor disease outcome during HIV infection in humans and Simian Immunodeficiency virus (SIV) in monkeys coincides with elevated IFN-I signatures. Infection with the persistent clone-13 strain of LCMV results in reduced containment of murine cytomegalovirus (MCMV) infection. Although anti-viral T cell or antibody responses were not directly measured in this scenario, this study agrees with the results reported by Honke and colleagues. It would be interesting to know whether persistent LCMV infection prevents enforced viral replication in CD169⁺ macrophages during MCMV as well as co-infection with additional viruses. Moreover, given the immunosuppressive role of IFN-I signaling during persistent LCMV infection, it would be interesting to know what role the Usp18 protein plays in promoting virus persistence. Further work is necessary to understand why Usp18 is not effective following sustained IFN-I signaling during persistent viral infection. Taken together, Honke et al. identify a novel mechanism by which IFN-I signaling promotes immune suppression during persistent virus infection. Moreover, this study contributes significantly to our understanding of how IFN-I signaling inhibits enforced viral replication and in turn prevents control of secondary viral infections following ongoing persistent viral infections.