Department of Microbiology and Immunology, University of Rochester School of Medicine and Dentistry, Rochester, New York, USA.
Department of Environmental Medicine, University of Rochester School of Medicine and Dentistry, Rochester, New York, USA.
Environ Health Perspect. 2021 Jan;129(1):17007. doi: 10.1289/EHP7699. Epub 2021 Jan 15.
Early life environmental exposures can have lasting effects on the function of the immune system and contribute to disease later in life. Epidemiological studies have linked early life exposure to xenobiotics that bind the aryl hydrocarbon receptor (AhR) with dysregulated immune responses later in life. Among the immune cells influenced by developmental activation of the AhR are T cells. Yet, the underlying affected cellular pathways via which activating the AhR early in life causes the responses of T cells to remain affected into adulthood remain unclear.
Our goal was to identify cellular mechanisms that drive impaired T-cell responses later in life following maternal exposure to an exogenous AhR ligand.
C57BL/6 mice were vertically exposed to the prototype AhR ligand, 2,3,7,8-tetrachlorodibenzo--dioxin (TCDD), throughout gestation and early postnatal life. The transcriptome and DNA methylation patterns were evaluated in T cells isolated from naïve and influenza A virus (IAV)-infected adult mice that were developmentally exposed to TCDD or vehicle control. We then assessed the influence of DNA methylation-altering drug therapies on the response of T cells from developmentally exposed mice to infection.
Gene and protein expression showed that developmental AhR activation reduced T-cell expansion and effector functions during IAV infection later in life. Furthermore, whole-genome bisulfite sequencing analyses revealed that developmental AhR activation durably programed DNA methylation patterns across the T-cell genome. Treatment of developmentally exposed offspring with DNA methylation-altering drugs alleviated some, but not all, of the impaired T-cell responses.
Taken together, these results indicate that skewed DNA methylation is one of the mechanisms by which early life exposures can durably change the function of T cells in mice. Furthermore, treatment with DNA methylation-altering drugs after the exposure restored some aspects of T-cell functional responsiveness. https://doi.org/10.1289/EHP7699.
早期生活环境暴露会对免疫系统的功能产生持久影响，并导致以后生活中的疾病。流行病学研究将早期生活中接触到的与芳烃受体（AhR）结合的外源化学物质与以后生活中免疫反应失调联系起来。在受 AhR 发育激活影响的免疫细胞中，有 T 细胞。然而，通过早期生活激活 AhR 导致 T 细胞的反应在成年后仍受影响的潜在受影响细胞途径尚不清楚。
我们的目标是确定母体暴露于外源性 AhR 配体后，在生命后期导致 T 细胞反应受损的细胞机制。
C57BL/6 小鼠通过垂直暴露于原型 AhR 配体 2,3,7,8-四氯二苯并二恶英（TCDD），在整个妊娠期和新生儿期早期。评估从发育上暴露于 TCDD或载体对照的幼稚和甲型流感病毒（IAV）感染的成年小鼠中分离出的 T 细胞的转录组和 DNA 甲基化模式。然后，我们评估了 DNA 甲基化改变药物治疗对发育性暴露于病毒的 T 细胞对感染反应的影响。
基因和蛋白质表达表明，早期 AhR 激活会减少生命后期 IAV 感染时 T 细胞的扩增和效应功能。此外，全基因组亚硫酸氢盐测序分析表明，早期 AhR 激活会在整个 T 细胞基因组中持久地编程 DNA 甲基化模式。用 DNA 甲基化改变药物治疗发育性暴露的后代缓解了一些，但不是所有，受损的 T 细胞反应。
综上所述，这些结果表明，偏斜的 DNA 甲基化是早期生活暴露可以持久改变小鼠 T 细胞功能的机制之一。此外，暴露后用 DNA 甲基化改变药物治疗恢复了 T 细胞功能反应的某些方面。https://doi.org/10.1289/EHP7699.
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