Does the Maternal Environment During Viral Infection and Inflammation Direct Fetal Gamma Delta T Cell Development and Function?

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Existing evidence emphasizes the importance of the role played by the maternal environment, particularly the intrauterine environment, in fetal and early development and in the trajectory of adult life. The understanding of the underlying molecular pathways and related biologic correlates is thus of critical importance to several institutes of the NIH. This application is in response to PAR-20-298, which highlights the importance of understanding the role of the maternal environment in the development of the immune system. To fully and innovatively examine this issue we think requires examination of cells at the interface between innate and adaptive immunity. A key component of this interface are γδT cells (GDT). These cells can be intimately located within tissues at the maternal-fetal interface, where they may be supportive of both pro and anti-inflammatory responses and may mediate adverse pregnancy or neonatal outcomes. Recent evidence suggests that these cells may play an important role in neonatal immunity. We have used a mouse model to study the development of GDT. These cells develop early in the thymus, beginning around day 14 of gestation. Day 17 of gestation is a critical timepoint for generation of specific functional subsets, e.g., expression of IL-17, of GDT. Therefore, GDT development is likely influenced by the maternal environment. Further, evidence suggests that GDT mediate anti-cancer and autoimmune responses in addition to protective immunity depending on their functional subset. Thus, in utero programming of GDT has long term consequences for the life of the offspring. We thus have the overall hypothesis, that maternal infectious and inflammatory responses are critical mediators of the immunologic milieu which regulates GDT development and function. To probe this hypothesis, we seek to utilize a mouse model of viral infection with Lymphocytic Choriomeningitis virus (LCMV). We have shown that acute maternal infection at mid gestation results in a persistent placental/decidual infection which is modified by local CD8 T cells. However, the response and regulation of local GDT is not known. Further, though the fetus appears to remain protected against productive infection, outcome of neonatal immunity in this situation has not been fully explored. Our group of experts in GDT cell development and maternal and fetal immunity seeks to use LCMV infection and to utilize the tools of multiparameter flow cytometry and single cell RNA seq to: i) determine the outcome of viral infection or inflammation on uterine and placental GDT presence and functional capacity, ii) determine the phenotype and function of neonatal GDT in response to maternal viral infection and iii) relate maternal infection, early GDT development and subsequent GDT-related response in mouse models of autoimmunity and cancer. These studies will contribute to growing data on the important influence of the maternal environmen on long term health. They will eventually impact our management of viral susceptibility and infection during pregnancy, vaccination of pregnant women, and the diagnosis and treatment of infants born to infected mothers.