Preconceptual paternal allergen exposure, offspring asthma, and pulmonary gamma/delta T cell function

“健康与疾病的发育起源”(DOHAD)假说认为，早期的生命暴露 (营养、环境、炎症)影响后代对一些非传染性疾病的易感性 疾病。过敏性哮喘是一种影响3亿人的疾病，其患病率继续上升。 与DOHaD假说一致，母亲和父亲的暴露可以影响高血压的风险和严重程度。 子代哮喘。母亲暴露于环境因素可通过改变 子代T细胞和树突状细胞的表观基因组。相比之下，虽然父亲的特定暴露(烟草烟雾， 在特定职业中的就业)改变人类后代哮喘的风险，影响后代的细胞类型 都是未知的。我们新的初步数据表明，怀孕前父亲的HDM暴露于 过敏原屋尘螨(HDM)与哮喘严重程度降低和Rorgt-2募集增加有关。 在后代中表达gd T细胞群，而后代gd T细胞的耗尽消除了保护作用 父亲过敏原暴露的影响。虽然父亲的暴露已被证明会影响后代 动物模型中的行为和/或代谢功能障碍的发展，我们创新的初步数据是 首先，证明父亲暴露在过敏原中会影响子代的慢性炎症反应。 由于gd T细胞耗尽逆转了父亲过敏原暴露的保护作用，我们假设父亲 HDM暴露通过改变表达Rorgt的gd的表型和功能降低子代哮喘的严重程度 T细胞群存在于肺中。这一创新假说将在两个独立但又相关的 明确的目标。目的1：确定表达Rorgt的gdT细胞是否必要且足以减少 暴露于HDM的父亲的后代中的呼吸道高反应性，我们将在gd中选择性地删除Rorgt 2)过继转移肺Rorgt+Gd T细胞群 从对照组或接触过敏原的父亲的后代中分离出来的病毒进入对照组小鼠的肺部。完全性哮喘 将评估表型以确定肺GdT细胞是否是必要的和/或足够的介质 父亲过敏原暴露介导的子代哮喘保护。目的2：构建基因调控基因 控制哮喘保护性肺GdT细胞的网络(GRN)。为此，从猪的后代中分离出的肺Gd T细胞 控制和接触过敏原的父亲将在过敏原致敏之前和之后被隔离，并使用 ScRNA-seq和scATAC-seq用于GRN构建。GRN将确定TF如何利用增强剂和 协调基因表达模式与哮喘保护相关。我们会确定哮喘是否- Gd T细胞的保护作用是由于亚群丰度的变化和/或功能的改变。一种理解 父亲的暴露可影响免疫细胞功能的细胞和分子机制 将促进公共健康，并开辟新的研究路线，包括治疗途径 哮喘和其他免疫紊乱(如自身免疫性、过敏性)和传染病。

The “Developmental Origin of Health and Disease” (DOHaD) hypothesis posits that early life exposures (nutritional, environmental, inflammatory) influence offspring susceptibility to a number of non-communicable diseases. Allergic asthma, a disease affecting >300 million people, continues to increase in prevalence. Consistent with the DoHAD hypothesis, maternal and paternal exposures can influence both risk and severity of offspring asthma. Maternal exposures to environmental factors can influence offspring asthma by modifying the epigenome in offspring T cells and dendritic cells. In contrast, while specific paternal exposures (tobacco smoke, employment in specific occupations) alter offspring asthma risk in humans, the cell types impacted in offspring are unknown. Our novel preliminary data demonstrate that pre-conceptual paternal HDM exposure to the allergen house dust mite (HDM) is associated with a reduced asthma severity and increased recruitment of Rorgt- expressing gd T cell populations in offspring, and that depletion of offspring gd T cells abrogates the protective effect of paternal allergen exposure. While paternal exposures have been demonstrated to influence offspring behavior, and/or development of metabolic dysfunction in animal models, our innovative preliminary data are the first to demonstrate that paternal exposures to allergens influence chronic inflammatory responses in offspring. As gd T cell depletion reversed the protective effects of paternal allergen exposure, we hypothesize that paternal HDM exposure reduces offspring asthma severity by altering the phenotype and function of Rorgt-expressing gd T cell populations present in the lung. This innovative hypothesis will be tested in two independent, yet related specific aims. Aim 1: To determine if Rorgt-expressing gd T cells are necessary and sufficient to reduce airway hyper-responsiveness in offspring of HDM-exposed fathers, we will 1) delete Rorgt selectively in gd T cells in offspring of allergen-exposed fathers, and 2) adoptively transfer lung Rorgt+ gd T cell populations isolated from offspring of control or allergen-exposed fathers into the lungs of control mice. The complete asthma phenotype will be assessed to determine if pulmonary gd T cells are necessary and/or sufficient mediators of paternal allergen-exposure-mediated protection from offspring asthma. Aim 2: Construct the gene regulatory networks (GRNs) governing asthma-protective lung gd T cells. To this end, lung gd T cells from offspring of control and allergen-exposed fathers will be isolated prior to, and after allergen sensitization, and profiled using scRNA-seq and scATAC-seq for GRN construction. The GRN will identify how TFs utilize enhancers and orchestrate gene expression patterns correlated with asthma protection. We will determine whether the asthma- protective role of gd T cells is due to changes in subset abundances and/or altered functionality. An understanding of the cellular and molecular mechanisms through which paternal exposures can influence immune cell function in offspring will advance public health and open up new lines of research, including therapeutic avenues, for asthma and other immune disorders (e.g. autoimmune, allergic) and infectious disease.