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.
