Project Summary Increasing evidence suggests that maternal inflammation/infection-induced immune activation (MIA) during pregnancy can lead to sustained, long-lasting changes in immune function of the offspring, which could alter disease susceptibility later in life. During pregnancy, the developing fetus is continuously exposed to a variety of factors at the maternal-fetal interface that can have a significant influence on fetal immune development. The fetal immune system is characterized by the development of innate and innate-like immune cells possessing highly specialized functions distinct from their adult-derived counterparts. One example, and the focus of this proposal, are the innate-like γδ T cells. γδ T cells are unusual tissue-resident T cells that play critical roles in infectious disease, tumor surveillance, and autoimmunity. Unlike their conventional αβ T cell counterparts, innate-like γδ T cell subsets are programmed to acquire function during thymic development, and they appear to retain this programming indefinitely. Interestingly, in both humans and mice some γδ T cell subsets are functionally programmed in the fetal thymus in carefully orchestrated developmental waves, and the best available data suggests these fetal-derived γδ T cell subsets are maintained as continuously self-renewing populations in the adult. These data suggest that innate-like fetal γδ T cell development is especially vulnerable to maternal immune activation during pregnancy. Here, we propose to examine whether maternal inflammation/infection during pregnancy will impact fetal thymic innate-like γδ T cell development, which in turn could have long-lasting effects on γδ T cell phenotype and function in neonates and/or adults. Our preliminary studies support the notion that maternal immune activation can have a significant effect on fetal thymic γδ T cell development and that this effect can persist to the neonatal stage. To test this hypothesis, we propose to combine a single cell proteogenomics workflow customized for γδ T cell analysis, and a clinically relevant model of viral lymphocytic choriomeningitis virus (LCMV) infection. We will use these tools and others to: i) delineate the effect of maternal immune activation on thymic γδ T cell transcriptional and epigenetic landscape at different gestational ages, ii) define the mechanisms through which maternal immune activation affects thymic γδ T cell development, and iii) determine the impact of a placenta-tropic virus infection on fetal γδ T cell development. The proposed studies represent the first critical and comprehensive assessment of the influence of maternal immune activation on γδ T development in the fetus and neonate. They will be critical in informing both our understanding of both γδ T cell biology, and in our understanding of how maternal environment shapes pre- natal immune development.

Gamma delta T cells are unusual T cells that play important roles in the immune response in mucosal tissues. Some gamma delta T cell subsets develop and acquire function only in the fetal thymus. We will use a mouse model to understand how maternal infection and inflammation during pregnancy influences the fetal thymic development of gamma delta T cells, and whether maternal infection/inflammation can result in long-lasting changes in gamma delta cell function in offspring.