Interferon Lambda Signals in Maternal Tissues to Exert Protective and Pathogenic Effects in a Gestational Stage-Dependent Manner.

Interferon lambda (IFN-λ) (type III IFN) is constitutively secreted from human placental cells in culture and reduces Zika virus (ZIKV) transplacental transmission in mice. However, the roles of IFN-λ during healthy pregnancy and in restricting congenital infection remain unclear. Here, we used mice lacking the IFN-λ receptor (Ifnlr1-/-) to generate pregnancies lacking either maternal or fetal IFN-λ responsiveness and found that the antiviral effect of IFN-λ resulted from signaling exclusively in maternal tissues. This protective effect depended on gestational stage, as infection earlier in pregnancy (E7 rather than E9) resulted in enhanced transplacental transmission of ZIKV. In Ifnar1-/- dams, which sustain robust ZIKV infection, maternal IFN-λ signaling caused fetal resorption and intrauterine growth restriction. Pregnancy pathology elicited by poly(I·C) treatment also was mediated by maternal IFN-λ signaling, specifically in maternal leukocytes, and also occurred in a gestational stage-dependent manner. These findings identify an unexpected effect of IFN-λ signaling, specifically in maternal (rather than placental or fetal) tissues, which is distinct from the pathogenic effects of IFN-αß (type I IFN) during pregnancy. These results highlight the complexity of immune signaling at the maternal-fetal interface, where disparate outcomes can result from signaling at different gestational stages. IMPORTANCE Pregnancy is an immunologically complex situation, which must balance protecting the fetus from maternal pathogens with preventing maternal immune rejection of non-self fetal and placental tissue. Cytokines, such as interferon lambda (IFN-λ), contribute to antiviral immunity at the maternal-fetal interface. We found in a mouse model of congenital Zika virus infection that IFN-λ can have either a protective antiviral effect or cause immune-mediated pathology, depending on the stage of gestation when IFN-λ signaling occurs. Remarkably, both the protective and pathogenic effects of IFN-λ occurred through signaling exclusively in maternal immune cells rather than in fetal or placental tissues or in other maternal cell types, identifying a new role for IFN-λ at the maternal-fetal interface.

Protective and Pathogenic Effects of Interferon Signaling During Pregnancy.

Immune regulation at the maternal-fetal interface is complex due to conflicting immunological objectives: protection of the fetus from maternal pathogens and prevention of immune-mediated rejection of the semiallogeneic fetus and placenta. Interferon (IFN) signaling plays an important role in restricting congenital infections as well as in the physiology of healthy pregnancies. In this review, we discuss the antiviral and pathogenic effects of type I IFN (IFN-α, IFN-ß), type II IFN (IFN-γ), and type III IFN (IFN-λ) during pregnancy, with an emphasis on mouse and non-human primate models of congenital Zika virus infection. In the context of these animal model systems, we examine the role of IFN signaling during healthy pregnancy. Finally, we review mechanisms by which dysregulated type I IFN responses contribute to poor pregnancy outcomes in humans with autoimmune disease, including interferonopathies and systemic lupus erythematosus.

Why Is IFN-λ Less Inflammatory? One IRF Decides.

Type I and type III interferons (IFNs) activate similar antiviral transcriptional programs, but the type I IFN response is more inflammatory. In this issue of Immunity, Forero et al. find that selective induction of the transcription factor IRF1 promotes proinflammatory chemokine expression downstream of type I IFN signaling.

Antiviral immunity backfires: Pathogenic effects of type I interferon signaling in fetal development.

Interferon-α/ß signaling is pathogenic in a mouse model of congenital Zika virus infection.