Pathogenic Implications for Autoimmune Mechanisms Derived by Comparative eQTL Analysis of CD4+ Versus CD8+ T cells

Inappropriate activation or inadequate regulation of CD4+ and CD8+ T cells may contribute to the initiation and progression of multiple autoimmune and inflammatory diseases. Studies on disease-associated genetic polymorphisms have highlighted the importance of biological context for many regulatory variants, which is particularly relevant in understanding the genetic regulation of the immune system and its cellular phenotypes. Here we show cell type-specific regulation of transcript levels of genes associated with several autoimmune diseases in CD4+ and CD8+ T cells including a trans-acting regulatory locus at chr12q13.2 containing the rs1131017 SNP in the RPS26 gene. Most remarkably, we identify a common missense variant in IL27, associated with type 1 diabetes that results in decreased functional activity of the protein and reduced expression levels of downstream IRF1 and STAT1 in CD4+ T cells only. Altogether, our results indicate that eQTL mapping in purified T cells provides novel functional insights into polymorphisms and pathways associated with autoimmune diseases. The study includes 304 individuals, no replicates. From each individual there are CD4+ and CD8+ T cell and peripheral blood samples extracted. The total number of good quality samples is 653, of which 293 have CD4+ T cell, 283 have CD8+ T cell and 77 have peripheral blood data. GSE59065 contains the DNA methylation data for samples with the same names.

CD4阳性T细胞（CD4+ T cells）与CD8阳性T细胞（CD8+ T cells）的异常活化或调控不足，可能参与多种自身免疫性与炎症性疾病的发生与进展。针对疾病相关遗传多态性的研究凸显了生物学背景对诸多调控变异的重要意义，这对于解析免疫系统及其细胞表型的遗传调控机制尤为关键。本研究揭示了CD4+ T细胞与CD8+ T细胞中多种自身免疫病相关基因转录水平的细胞类型特异性调控模式，其中包括位于12号染色体q13.2区域、包含RPS26基因内rs1131017单核苷酸多态性（SNP）的反式作用调控位点。尤为值得关注的是，我们鉴定出一种与1型糖尿病相关的IL27基因常见错义变异，该变异仅会降低CD4+ T细胞中该蛋白的功能活性，并下调下游干扰素调节因子1（IRF1）与信号转导与转录激活因子1（STAT1）的表达水平。综上，本研究结果表明，在纯化T细胞中开展表达数量性状位点定位（eQTL mapping），可为自身免疫病相关的多态性与通路研究提供全新的功能视角。

本研究共纳入304名受试者，未设置重复实验。从每名受试者体内均提取了CD4+ T细胞、CD8+ T细胞及外周血样本。最终符合质量标准的有效样本共计653份，其中293份带有CD4+ T细胞检测数据、283份带有CD8+ T细胞检测数据，77份带有外周血相关数据。GSE59065数据集包含与上述样本命名一致的样本的DNA甲基化数据。