Intersection of population variation and autoimmunity genetics in human T cell activation.
Intersection of population variation and autoimmunity genetics in human T cell activation.
复制标题
DOI：
10.1126/science.1254665
复制
发表时间：
2014-09-12
期刊：
影响因子：
--
通讯作者：
Benoist C
中科院分区：
文献类型：
--
作者：
Ye CJ;Feng T;Kwon HK;Raj T;Wilson MT;Asinovski N;McCabe C;Lee MH;Frohlich I;Paik HI;Zaitlen N;Hacohen N;Stranger B;De Jager P;Mathis D;Regev A;Benoist C
T淋巴细胞被抗原激活的条件适应性免疫应答和免疫病理学，但我们对它在人类中的变异及其遗传或环境根源知之甚少。我们分析了来自欧洲、亚洲和非洲血统的348名健康受试者在无偏激活或Th 17条件下CD 4 + T细胞的基因表达。我们观察到个体间的变异性，最显着的细胞因子转录，具有明显的偏见的基础上的祖先，并遵循模式比简单的Th 1/2/17分区更复杂。我们确定了39个基因位点，特别是在顺式与激活基因表达。我们进一步精细定位和验证了一个单碱基变异，它调节YY 1结合和控制自身免疫相关IL 2 RA基因的增强子元件的活性，影响其在活化T细胞中的活性，但不影响调节T细胞的活性。因此，个体间的变异性影响T辅助细胞活化的基本免疫过程，与自身免疫性疾病有重要联系。
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 Th17 conditions from 348 healthy subjects representing European, Asian and African ancestries. We observed inter-individual variability, most marked for cytokine transcripts, with clear biases on the basis of ancestry, and following patterns more complex than simple Th1/2/17 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, inter-individual variability affects the fundamental immunologic process of T helper activation, with important connections to autoimmune disease.