Broad Institute of Massachusetts Institute of Technology (MIT) and Harvard, Cambridge, MA 02142, USA.
Division of Immunology, Department of Microbiology and Immunobiology, Harvard Medical School, Boston, MA 02115, USA.
Science. 2014 Sep 12;345(6202):1254665. doi: 10.1126/science.1254665.
T lymphocyte activation by antigen conditions adaptive immune responses and immunopathologies, but we know little about its variation in humans and its genetic or environmental roots. We analyzed gene expression in CD4(+) T cells during unbiased activation or in T helper 17 (T(H)17) conditions from 348 healthy participants representing European, Asian, and African ancestries. We observed interindividual variability, most marked for cytokine transcripts, with clear biases on the basis of ancestry, and following patterns more complex than simple T(H)1/2/17 partitions. We identified 39 genetic loci specifically associated in cis with activated gene expression. We further fine-mapped and validated a single-base variant that modulates YY1 binding and the activity of an enhancer element controlling the autoimmune-associated IL2RA gene, affecting its activity in activated but not regulatory T cells. Thus, interindividual variability affects the fundamental immunologic process of T helper activation, with important connections to autoimmune disease.
T 淋巴细胞被抗原激活是适应性免疫应答和免疫病理学的条件，但我们对人类 T 淋巴细胞的变异及其遗传或环境根源知之甚少。我们分析了 348 名代表欧洲、亚洲和非洲血统的健康参与者在无偏激活或 T 辅助 17（T(H)17）条件下 CD4(+) T 细胞中的基因表达。我们观察到个体间的可变性，细胞因子转录本最为明显，以祖因为基础的明显偏差，遵循的模式比简单的 T(H)1/2/17 分区更为复杂。我们鉴定了 39 个与基因表达的顺式激活相关的特定遗传位点。我们进一步精细定位和验证了一个单碱基变异，该变异调节 YY1 结合和控制自身免疫相关 IL2RA 基因的增强子元件的活性，影响其在激活而非调节性 T 细胞中的活性。因此，个体间的可变性影响 T 辅助激活的基本免疫过程，与自身免疫性疾病有重要联系。
