The central nervous system and maternal-fetal interface are challenged with protecting from pathogeninsult while limiting immunopathology. Previous work has defined how anatomical structures and regulation of immune responses by resident immune cells contribute to this balance. However, the contribution of tissue-resident non-immune cells within these barriers remains understudied. By employing cutting edge human and mouse models, I was able to maintain three-dimensional structures that are present in tissues, such as neural rosettes found in developing brains to address the contribution of these non-immune cells. Moreover, these models allowed me to mimic physiologically relevant functions, such as migration of fetal extravillous trophoblasts into the maternal uterus during implantation. In both models, there are a diverse range of cell types that can contribute to immune responses. Using these models allowed for intercellular communication, and thus advanced our ability to evaluate interferon responses using in-vitro systems that closely model in-vivo settings. My thesis work highlights the delicate balance of interferon signaling to avoid unwarranted responses that can be detrimental to the host. My work revealed that these responses rely on tissue architecture and intercellular communication. Specifically, infection of forebrain organoids or mouse models with La Crosse virus revealed mechanisms of protective interferon responses. In contrast, IFNb exposure of extravillous trophoblast limited vascular remodeling, which is crucial for successful implantation. By exemplifying both protective effects (forebrain organoid and mouse models) and pathogenic consequences (implantation-on-a-chip) of robust IFN responses, future studies should focus on how balanced immune responses are regulated.