Postnatal administration of S-adenosylmethionine restores developmental AHR activation-induced deficits in CD8+ T cell function during influenza A virus infection.
Postnatal administration of S-adenosylmethionine restores developmental AHR activation-induced deficits in CD8+ T cell function during influenza A virus infection.
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出生后给予 S-腺苷甲硫氨酸可恢复甲型流感病毒感染期间发育性 AHR 激活诱导的 CD8 T 细胞功能缺陷。
DOI：
10.1093/toxsci/kfad019
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发表时间：
2023
期刊：
影响因子：
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通讯作者：
Lawrence,BPaige
中科院分区：
文献类型：
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作者：
Post,ChristinaM;Myers,JasonR;Winans,Bethany;Lawrence,BPaige
发育阶段的暴露可能会影响终生健康；然而，由于对细胞机制的了解不足，抵消负面后果是具有挑战性的。芳香烃受体(AHR)结合了许多小分子，包括许多污染物。发育过程中暴露于标志性环境AHR配体2，3，7，8-四氯二苯并对二恶英(TCDD)显著抑制成年后代对甲型流感病毒的适应性免疫反应。CD8+细胞毒性T淋巴细胞(CTL)对于感染的成功解决至关重要，这取决于其产生的数量和功能的复杂性。先前的研究表明，发育中AHR的激活显著减少了病毒特异性CD8+T细胞的数量，但对其功能的影响尚不清楚。其他研究表明，发育暴露与CD8+T细胞DNA甲基化的差异有关。然而，缺乏经验证据表明DNA甲基化的差异与CD8+T细胞功能改变存在因果关系。这两个目标是确定发育中AHR的激活是否影响CTL功能，以及甲基化的差异是否有助于降低CD8+T细胞对感染的反应。发育中AHR的触发显著降低了CTL的多功能性，并改变了CD8+T细胞的转录程序。增加DNA甲基化的S-腺苷蛋氨酸，而不是减少DNA甲基化的ZeBularine，恢复了多种功能，并增加了病毒特异性CD8+T细胞的数量。这些发现表明，由于发育过程中暴露于AHR结合的化学物质而导致的甲基化减少，有助于在以后的生活中抗病毒CD8+CTL功能的持久变化。因此，儿童暴露在环境化学品中的有害后果并不是永久不变的，这为采取干预策略改善健康打开了大门。
Developmental exposures can influence life-long health; yet, counteracting negative consequences is challenging due to poor understanding of cellular mechanisms. The aryl hydrocarbon receptor (AHR) binds many small molecules, including numerous pollutants. Developmental exposure to the signature environmental AHR ligand 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) significantly dampens adaptive immune responses to influenza A virus in adult offspring. CD8+ cytotoxic T lymphocytes (CTL) are crucial for successful infection resolution, which depends on the number generated and the complexity of their functionality. Prior studies showed developmental AHR activation significantly reduced the number of virus-specific CD8+ T cells, but impact on their functions is less clear. Other studies showed developmental exposure was associated with differences in DNA methylation in CD8+ T cells. Yet, empirical evidence that differences in DNA methylation are causally related to altered CD8+ T-cell function is lacking. The 2 objectives were to ascertain whether developmental AHR activation affects CTL function, and whether differences in methylation contribute to reduced CD8+ T-cell responses to infection. Developmental AHR triggering significantly reduced CTL polyfunctionality, and modified the transcriptional program of CD8+ T cells. S-adenosylmethionine, which increases DNA methylation, but not Zebularine, which diminishes DNA methylation, restored polyfunctionality and boosted the number of virus-specific CD8+ T cells. These findings suggest that diminished methylation, initiated by developmental exposure to an AHR-binding chemical, contributes to durable changes in antiviral CD8+ CTL functions later in life. Thus, deleterious consequence of development exposure to environmental chemicals is not permanently fixed, opening the door for interventional strategies to improve health.