Microbiota-dependent IFN-L controls uterine and placental immunity

Precise regulation of uterine immunity is required to support fundamental processes including reproduction and pathogen protection. How the local milieu and constitutive stressors, including the cervicovaginal microbiota, shape the delicate balance underlying uterine immunity is poorly understood. Here, we found that the cervicovaginal microbiota promotes both local immunity and the immunoregulatory activity of interferon lambda (IFN-L) in the uterus. Using murine models, we found a keystone role for IFN-L in constraining the immune tone of this site, in particular of innate lymphoid cells and Th17 cells. Further, in the context of pregnancy, IFN-L enhanced antibacterial responses at maternal-fetal barriers to Streptococcus agalactiae infection, thereby controlling fetal and neonatal transmission. Collectively, this work uncovered how IFN-L integrates microbial signals under both steady state and pregnancy conditions and mediates the essential functions of the uterine immune system – antimicrobial protection and immunoregulation.