Education of the fetal immune system by inherited maternal cells

人类胎儿在整个妊娠期经历复杂的免疫发育，母体免疫系统在妊娠期发育。 系统与胎儿密切相互作用，为分娩做准备，最明显的是以经胎盘的形式。 抗体的运输。然而，很少有人研究子宫内获得性母体内发育不良对功能的影响。 微嵌合体（MMc）细胞对胎儿免疫发育的影响。胎儿T细胞开始聚集在淋巴结中， 在妊娠10-12周的外周血中，早在13周的胎儿中就发现了母体细胞。 这表明胎儿和母体细胞同时进入关键的免疫空间。我们有 先前在脐带血的许多细胞亚群中鉴定出MMc，包括T细胞和抗原呈递细胞 （APC）。基于这些观察，我们提出了一种新的范式，其中胎儿免疫系统是 通过这种母体移植深刻地塑造了（i）功能性母体T细胞的获得，以及（ii）教育 胎儿T细胞被母体APC感染。在南非的一个队列中，我们发现孕产妇艾滋病毒与 在妊娠期开始抗逆转录病毒治疗时，出生MMc降低， 在妊娠前开始，出生时MMc水平与未暴露于HIV的婴儿相似。这些数据表明 母体免疫系统与胎儿获得的MMc数量之间存在联系， 妊娠前半期的重建恢复了母体移植物。除了这些观察之外， 母体T细胞区室与MMc T细胞的大小或多样性之间的关系尚不清楚。如果 母体T细胞转移是一种罕见的事件，MMc T细胞可能来源于一组有限的创始克隆，导致 限制性MMc曲目。或者，如果母体细胞以不受限制的方式运输，它们可能会反映 母体T细胞库的完全多样性，类似于由免疫缺陷病毒获得的母体IgG的广泛特异性。 胎儿，与出生后感染易感性的潜在影响。因此，我们将检验以下假设： 母体T细胞以不受限制的方式运输，并广泛反映了母体早期T细胞库的多样性。 怀孕期间此外，MMc APC对胎儿免疫发育的影响完全未被探索。胎儿 相对于成熟的成人APC，APC具有受损的炎性细胞因子的产生，导致优先的 胎儿T细胞分化为Th 2效应或调节性T细胞。相反，我们假设MMc APC 通过共享的HLA与胎儿T细胞相互作用将驱动胎儿T细胞分化为保护性Th 1效应子 细胞为了验证这些假设，我们将招募一组前瞻性的美国孕妇， 艾滋病毒从孕早期高质量的采样。利用我们强大的单细胞管道，我们将分离 来自胎儿脐带血的罕见母体细胞，并表征它们与母体T细胞区室的关系 以及它们对胎儿T细胞应答的潜在影响。对这些母体细胞的作用有了更好的理解 对胎儿和新生儿的健康有重要的影响，包括 母亲免疫和艾滋病毒暴露和未暴露的后代对感染的易感性。

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.