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）会影响表观遗传调节事件，导致后代对甲型流感病毒感染的反应存在长期缺陷。缺陷包括病毒特异性CD 8 + 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：该项目的目的是了解在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CD 8 + T细胞对感染的反应长期受损。虽然已知表观遗传机制调节免疫细胞中的基因表达，但发育期间不适当的AhR激活通过表观遗传机制引起永久性功能变化的想法是一种新的范式。拟议研究的总体假设是，发育期间不适当的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CD 8 + T细胞功能的长期降低。具体目的：1）为了鉴定AhR的发育和谱系特异性靶标，其导致CD 8 + T细胞对感染的应答能力的持久降低，我们将使用祖细胞移植、谱系特异性基因消除和过继转移的组合来确定特定造血谱系中重编程的贡献。2)为了确定基因的目标，其表达差异沉默或激活发育暴露于二恶英，我们将定义AhR介导的CpG甲基化和共价组蛋白修饰的ifng基因座的变化，并使用新的全基因组方法来确定其他受影响的表观遗传调控基因。3)为了确定由AhR调控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，以及这些变化是否有助于受损的CD 8？T细胞功能，如受损的干扰素？感染后生产。意义：拟议的研究涉及与全球人类健康相关但未得到充分关注的领域。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，产前和生命早期暴露于污染物是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在正常的造血中起作用，并且发育暴露于AhR配体使免疫功能的许多方面失调。此外，TCDD和其他AhR配体会破坏其他组织的发育，因此这些研究的结果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.