Education of the fetal immune system by inherited maternal cells

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The human fetus undergoes complex immune development throughout gestation, and the maternal immune system interacts closely with that of her fetus in preparation for birth most notably in the form of transplacental transport of antibodies. Little studied, however, is the functional impact of in utero acquired maternal microchimeric (MMc) cells on fetal immune development. Fetal T cells begin to populate the lymph nodes and peripheral blood at 10-12 weeks’ gestation, and maternal cells are found in the fetus as early as 13 weeks’ gestation, suggesting that fetal and maternal cells access key immunologic spaces concurrently. We have previously identified MMc in many cell subsets from cord blood, including T cells and antigen presenting cells (APCs). Based on these observations, we propose a novel paradigm in which the fetal immune system is profoundly shaped by this maternal graft via (i) the acquisition of functional maternal T cells, and (ii) the education of fetal T cells by maternal APCs. In a South African cohort, we found that maternal HIV was associated with decreased birth MMc when antiretroviral therapy was initiated during pregnancy, whereas, when therapy was initiated prior to the pregnancy, the level of birth MMc was similar to HIV unexposed infants. These data suggest a link between the maternal immune system and the amount of MMc acquired by her fetus, where immune reconstitution in the first half of pregnancy restored the maternal graft. Outside of these observations, the relationship between the maternal T cell compartment and the size or diversity of MMc T cells is unknown. If maternal T cell transfer is a rare event, MMc T cells may be derived from a limited set of founding clones leading to a restricted MMc repertoire. Alternatively, if maternal cells traffic in an unrestricted fashion, they may reflect the full diversity of the maternal T cell repertoire, akin to the broad specificity of maternal IgG acquired by the fetus, with potential implications for postnatal susceptibility to infection. We will therefore test the hypothesis that maternal T cells traffic in an unrestricted fashion and broadly reflect the diversity of the maternal repertoire early in pregnancy. In addition, the impact of MMc APCs on fetal immune development is entirely unexplored. Fetal APC have impaired production of inflammatory cytokines relative to mature adult APC, resulting in preferential differentiation of fetal T cells into Th2 effector or regulatory T cells. In contrast, we hypothesize that MMc APC interacting with fetal T cells via shared HLA will drive the differentiation of fetal T cells into protective Th1 effector cells. To test these hypotheses, we will enroll a prospective cohort of US pregnant women living with and without HIV followed from first trimester with high quality sampling. Utilizing our robust single cell pipeline we will isolate rare maternal cells from fetal cord blood and characterize their relationship to the maternal T cell compartment and their potential effect on fetal T cell responses. An improved understanding of the role of these maternal cells in shaping fetal immunity would have significant implications for fetal and neonatal health, including timing of maternal immunization and susceptibility to infection in both HIV exposed and unexposed offspring.