Murdoch Children's Research Institute, and Department of Paediatrics, University of Melbourne, Royal Children's Hospital, Flemington Road, Parkville, VIC, Australia.
Wal-yan Respiratory Research Centre, Telethon Kids Institute, Perth, Australia.
Immunol Cell Biol. 2023 May;101(5):397-411. doi: 10.1111/imcb.12628. Epub 2023 Mar 1.
Childhood is a critical period of immune development. During this time, naïve CD4 (nCD4) T cells undergo programmed cell differentiation, mediated by epigenetic changes, in response to external stimuli leading to a baseline homeostatic state that may determine lifelong disease risk. However, the ontogeny of epigenetic signatures associated with CD4 T cell activation during key developmental periods are yet to be described. We investigated genome-wide DNA methylation (DNAm) changes associated with nCD4 T activation following 72 h culture in media+anti-CD3/CD28 beads in healthy infants (aged 12 months, n = 18) and adolescents (aged 10-15 years, n = 15). We integrated these data with transcriptomic and cytokine profiling from the same samples. nCD4 T cells from both age groups show similar extensive epigenetic reprogramming following activation, with the majority of genes involved in the T cell receptor signaling pathway associated with differential methylation. Additionally, we identified differentially methylated probes showing age-specific responses, that is, responses in only infants or adolescents, including within a cluster of T cell receptor (TCR) genes. These encoded several TCR alpha joining (TRAJ), and TCR alpha variable (TRAV) genes. Cytokine data analysis following stimulation revealed enhanced release of IFN-γ, IL-2 and IL-10, in nCD4 T cells from adolescents compared with infants. Overlapping differential methylation and cytokine responses identified four probes potentially underpinning these age-specific responses. We show that DNAm in nCD4T cells in response to activation is dynamic in infancy and adolescence, with additional evidence for age-specific effects potentially driving variation in cytokine responses between these ages.
儿童期是免疫系统发育的关键时期。在此期间，幼稚 CD4（nCD4）T 细胞在外源性刺激的作用下，通过表观遗传变化进行程序性细胞分化，导致一种基础的平衡状态，这种状态可能决定终生的疾病风险。然而，与关键发育阶段 CD4 T 细胞激活相关的表观遗传特征的个体发生仍有待描述。我们研究了在健康婴儿（12 个月龄，n=18）和青少年（10-15 岁，n=15）中，nCD4 T 细胞在经过 72 小时的培养和抗 CD3/CD28 珠刺激后，与 nCD4 T 细胞激活相关的全基因组 DNA 甲基化（DNAm）变化。我们将这些数据与同一样本的转录组和细胞因子谱进行了整合。来自两个年龄组的 nCD4 T 细胞在激活后都表现出类似的广泛表观遗传重编程，大多数涉及 T 细胞受体信号通路的基因与差异甲基化有关。此外，我们还鉴定了具有年龄特异性反应的差异甲基化探针，即仅在婴儿或青少年中存在反应的探针，包括在 T 细胞受体（TCR）基因簇中。这些基因编码了几个 TCR alpha 连接（TRAJ）和 TCR alpha 可变（TRAV）基因。刺激后的细胞因子数据分析显示，与婴儿相比，青少年的 nCD4 T 细胞中 IFN-γ、IL-2 和 IL-10 的释放增强。重叠的差异甲基化和细胞因子反应鉴定了四个可能为这些年龄特异性反应提供基础的探针。我们表明，nCD4T 细胞对激活的 DNAm 在婴儿期和青春期是动态的，并且有额外的证据表明年龄特异性效应可能会导致这两个年龄段之间细胞因子反应的差异。
