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

Interferon lambda (IFN-lambda) (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-lambda during healthy pregnancy and in restricting congenital infection remain unclear. Here, we used mice lacking the IFN-lambda receptor (IfnIr1(-/-)) to generate pregnancies lacking either maternal or fetal IFN-lambda responsiveness and found that the antiviral effect of IFN-lambda 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-lambda signaling caused fetal resorption and intrauterine growth restriction. Pregnancy pathology elicited by poly(I.C) treatment also was mediated by maternal IFN-lambda signaling, specifically in maternal leukocytes, and also occurred in a gestational stage-dependent manner. These findings identify an unexpected effect of IFN-lambda signaling, specifically in maternal (rather than placental or fetal) tissues, which is distinct from the pathogenic effects of IFN-alpha beta (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-lambda), contribute to antiviral immunity at the maternal-fetal interface. We found in a mouse model of congenital Zika virus infection that IFN-lambda can have either a protective antiviral effect or cause immune-mediated pathology, depending on the stage of gestation when IFN-lambda signaling occurs. Remarkably, both the protective and pathogenic effects of IFN-lambda 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-lambda at the maternal-fetal interface.