Genetic studies have revealed that autoimmune susceptibility variants are over-represented in memory CD4+ T cell regulatory elements1-3. Understanding how genetic variation affects gene expression in different T cell physiological states is essential for deciphering genetic mechanisms of autoimmunity4,5. Here, we characterized the dynamics of genetic regulatory effects at eight time points during memory CD4+ T cell activation with high-depth RNA-seq in healthy individuals. We discovered widespread, dynamic allele-specific expression across the genome, where the balance of alleles changes over time. These genes were enriched fourfold within autoimmune loci. We found pervasive dynamic regulatory effects within six HLA genes. HLA-DQB1 alleles had one of three distinct transcriptional regulatory programs. Using CRISPR-Cas9 genomic editing we demonstrated that a promoter variant is causal for T cell-specific control of HLA-DQB1 expression. Our study shows that genetic variation in cis-regulatory elements affects gene expression in a manner dependent on lymphocyte activation status, contributing to the interindividual complexity of immune responses.

中文翻译：

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HLA 和其他自身免疫位点的等位基因特异性表达在 T 细胞激活过程中动态变化。

遗传学研究表明，自身免疫易感性变异在记忆 CD4+ T 细胞调节元件中过多出现1-3。了解遗传变异如何影响不同 T 细胞生理状态下的基因表达对于破译自身免疫的遗传机制至关重要 4,5。在这里，我们通过深度 RNA-seq 描述了健康个体记忆 CD4+ T 细胞激活过程中 8 个时间点的遗传调控效应的动态。我们发现整个基因组中存在广泛的、动态的等位基因特异性表达，其中等位基因的平衡随着时间的推移而变化。这些基因在自身免疫位点内富集了四倍。我们发现六个 HLA 基因内普遍存在动态调节作用。HLA-DQB1 等位基因具有三种不同的转录调控程序之一。使用 CRISPR-Cas9 基因组编辑，我们证明启动子变异是 T 细胞特异性控制 HLA-DQB1 表达的原因。我们的研究表明，顺式调控元件的遗传变异以依赖于淋巴细胞激活状态的方式影响基因表达，从而导致个体间免疫反应的复杂性。