Environmental Influences on Epigenetic Immune Programming

描述（由申请人提供）：我们已经获得证据表明，发育暴露于ahr特异性配体TCDD（二恶英）会影响表观遗传调控事件，导致后代对甲型流感病毒感染的反应出现长期缺陷。缺陷包括病毒特异性CD8+ T细胞的扩增和分化减少，抗病毒细胞因子IFN的产生受损。目的/假设：本项目的目的是了解胎儿和新生儿发育过程中通过AhR传递的环境信号如何导致CD8+ T细胞对感染反应的长期损害。虽然已知表观遗传机制调节免疫细胞中的基因表达，但发育过程中不适当的AhR激活通过表观遗传机制导致永久性功能变化的想法是一种新的范式。提出的研究的总体假设是，发育过程中不适当的AhR激活通过表观遗传机制干扰免疫系统的编程，导致基因表达的永久性缺陷，导致CD8+ T细胞功能的长期降低。具体目的：1)为了确定导致CD8+ T细胞对感染反应能力长期降低的AhR的发育和谱系特异性靶点，我们将使用祖细胞移植、谱系特异性基因切除和过继转移的组合来确定在特定造血谱系中重编程的贡献。2)为了确定表达因二恶英发育暴露而差异沉默或激活的基因靶点，我们将定义ahr介导的CpG甲基化和ifing位点共价组蛋白修饰的变化，并使用新的全基因组方法来确定受影响的其他表观遗传调控基因。3)为了确定由AhR调节的表观遗传调控途径，我们将使用药理学和遗传学方法来确定哪些DNA甲基转移酶受到影响，以及这些变化是否导致CD8受损？T细胞功能，如IFN？感染后的生产。意义：拟议的研究涉及一个与全球人类健康相关但未得到充分重视的领域。流感和其他病毒感染继续对全球健康构成重大威胁。有证据表明，产前和生命早期接触污染物是导致感染后临床结果较差的被忽视的因素。此外，AhR影响表观遗传编程的想法是创新的，具有广泛的生物学意义，因为AhR在正常造血中发挥作用，并且发育暴露于AhR配体会解除免疫功能的许多方面。此外，TCDD和其他AhR配体破坏其他组织的发育，因此这些研究的发现将有助于我们更好地了解AhR配体如何影响全身细胞，并将提供有关AhR正常生理作用的新信息。

DESCRIPTION (provided by applicant): We have obtained evidence that developmental exposure to the AhR-specific ligand TCDD (dioxin) affects epigenetically-regulated events leading to long-lasting defects in the offspring's response to influenza A virus infection. Defects include reduced expansion and differentiation of virus-specific CD8+ T cells, impaired production of the antiviral cytokine IFN?. Objectives/Hypothesis: The purpose of this project is to understand how environmental signals delivered via AhR during fetal and neonatal development cause long-lasting impairment of CD8+ T cell responses to infection. Although epigenetic mechanisms are known to regulate gene expression in immune cells, the idea that inappropriate AhR activation during development causes permanent functional changes via an epigenetic mechanism is a novel paradigm. The overall hypothesis for the proposed studies is that inappropriate AhR activation during development interferes with the programming of the immune system via epigenetic mechanisms, resulting in permanent defects in gene expression that lead to long-lasting reductions in CD8+ T cell function. Specific Aims:1) To identify the developmental and lineage-specific targets of AhR that cause long-lasting reductions in the capacity of CD8+ T cells to respond to infection, we will determine the contribution of reprogramming in specific hematopoietic lineages using a combination of progenitor cell transplantation, lineage-specific gene ablation, and adoptive transfer. 2) To identify gene targets whose expression is differentially silenced or activated by developmental exposure to dioxin, we will define AhR-mediated changes in CpG methylation and covalent histone modifications of the ifng locus, and use novel genome-wide approaches to identify additional epigenetically-regulated genes that are affected. 3) To identify epigenetic regulatory pathways modulated by AhR we will use pharmacological and genetic approaches to determine which DNA methyltransferases are affected and whether these changes contribute to impaired CD8? T cell functions, such as impaired IFN? production following infection. Significance: The proposed studies address an area that is relevant to global human health but has received inadequate attention. Influenza and other viral infections continue to pose significant global health threats. Evidence points to prenatal and early life exposure to pollutants as overlooked contributors to poorer clinical outcomes following infection. Moreover, the idea that AhR impacts epigenetic programming is innovative and has broad biological significance, as AhR plays a role in normal hematopoiesis, and developmental exposure to AhR ligands deregulates many aspects of immune function. Moreover, TCDD and other AhR ligands disrupt development of other tissues, thus findings from these studies will help us better understand how AhR ligands impact cells throughout the body, and will provide new information regarding the normal physiological role of AhR.