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

现有的证据强调了母体环境所起的重要作用，特别是 宫内环境，在胎儿和早期发育，并在成年生活的轨迹。的理解 因此，潜在的分子途径和相关的生物学相关物对于几种 NIH的研究所。本申请是对PAR-20-298的回应，该申请强调了以下方面的重要性： 了解母体环境在免疫系统发育中的作用。充分和 创新地研究这个问题，我们认为需要检查细胞之间的界面先天和 适应性免疫该界面的关键组分是γδT细胞（GDT）。这些细胞可以紧密地位于 在母胎界面的组织内，它们可能同时支持促炎和抗炎作用 反应，并可能介导不良妊娠或新生儿结局。 最近的证据表明，这些细胞可能在新生儿免疫中发挥重要作用。我们使用了 小鼠模型，以研究GDT的发展。这些细胞在胸腺早期发育， 14怀孕妊娠第17天是产生特定功能亚群的关键时间点，例如， IL-17和GDT的表达。因此，GDT的发展可能受到母体环境的影响。 此外，有证据表明，GDT介导的抗癌和自身免疫反应，除了保护性 免疫力取决于其功能子集。因此，在子宫内编程的GDT具有长期的后果 为子孙后代的生活。因此，我们有一个总体假设，即母体感染性和炎症性 免疫应答是调节GDT发育和功能的免疫环境的关键介质。到 为了探索这一假说，我们试图利用病毒感染淋巴细胞性脉络丛脑膜炎的小鼠模型 病毒（LCMV）。我们已经证明，妊娠中期的急性母体感染会导致持续的 胎盘/蜕膜感染，其被局部CD 8 T细胞修饰。然而，应对和监管 本地GDT未知。此外，虽然胎儿似乎仍然受到保护，免受生产性感染， 在这种情况下，新生儿免疫的结果尚未得到充分探讨。我们的GDT电池专家团队 发展和母亲和胎儿的免疫寻求使用LCMV感染，并利用工具， 多参数流式细胞术和单细胞RNA测序，以：i）确定病毒感染的结果，或 炎症对子宫和胎盘GDT存在和功能能力的影响，ii）确定表型和 新生儿GDT响应母体病毒感染的功能和iii）相关的母体感染，早期GDT 在自身免疫和癌症的小鼠模型中的发展和随后的GDT相关反应。这些 这些研究将有助于提供越来越多的数据，说明产妇保健对长期健康的重要影响。 它们最终将影响我们在怀孕期间对病毒易感性和感染的管理， 对孕妇的诊断和治疗，以及对受感染母亲所生婴儿的诊断和治疗。

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.