Early life exposures shape the CD4+ T cell transcriptome, influencing proliferation, differentiation, and mitochondrial dynamics later in life
Early life exposures shape the CD4+ T cell transcriptome, influencing proliferation, differentiation, and mitochondrial dynamics later in life
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DOI：
10.1038/s41598-019-47866-2
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发表时间：
2019-08-07
影响因子：
4.6
通讯作者：
Lawrence, B. Paige
中科院分区：
文献类型：
--
作者：
Burke, Catherine G.;Myers, Jason R.;Lawrence, B. Paige
生命早期的环境暴露会导致免疫系统功能的持久变化，并可能导致生命后期的疾病。环境因素的作用方式之一是通过细胞受体。芳香烃受体（AHR）由免疫细胞表达并结合许多异生物质。早期接触结合AHR的化学物质会损害成年后CD4（+）T细胞对甲型流感病毒（IAV）感染的反应。然而，这些持久变化的细胞机制仍然不清楚。分类的CD4（+）T细胞的转录组学分析确定了参与增殖、分化和代谢途径的基因的变化与发育期间触发AHR相关。功能性生物测定证实，来自受感染发育暴露后代的CD4（+）T细胞表现出增殖、分化和细胞代谢降低。因此，发育性AHR激活通过影响整合的细胞通路在以后的生活中塑造T细胞应答能力，这共同改变了以后的生活中的应答。鉴于T细胞代谢的协调变化对于T细胞对许多挑战的反应至关重要，并且人类不断暴露于许多不同类型的AHR配体，这对AHR信号传导，特别是在发育期间，如何持久地影响T细胞介导的免疫应答具有深远的影响。
Early life environmental exposures drive lasting changes to the function of the immune system and can contribute to disease later in life. One of the ways environmental factors act is through cellular receptors. The aryl hydrocarbon receptor (AHR) is expressed by immune cells and binds numerous xenobiotics. Early life exposure to chemicals that bind the AHR impairs CD4(+) T cell responses to influenza A virus (IAV) infection in adulthood. However, the cellular mechanisms that underlie these durable changes remain poorly defined. Transcriptomic profiling of sorted CD4(+) T cells identified changes in genes involved in proliferation, differentiation, and metabolic pathways were associated with triggering AHR during development. Functional bioassays confirmed that CD4(+) T cells from infected developmentally exposed offspring exhibit reduced proliferation, differentiation, and cellular metabolism. Thus, developmental AHR activation shapes T cell responsive capacity later in life by affecting integrated cellular pathways, which collectively alter responses later in life. Given that coordinated shifts in T cell metabolism are essential for T cell responses to numerous challenges, and that humans are constantly exposed to many different types of AHR ligands, this has far-reaching implications for how AHR signaling, particularly during development, durably influences T cell mediated immune responses across the lifespan.