Division of Infectious Diseases, Advanced Clinical Research Center International Research Center for Infectious Diseases.
Research Center for Asian Infectious Diseases.
J Infect Dis. 2015 Jan 1;211(1):28-39. doi: 10.1093/infdis/jiu376. Epub 2014 Jul 7.
The molecular mechanisms for IL2 gene-specific dysregulation during chronic human immunodeficiency virus type 1 (HIV-1) infection are unknown. Here, we investigated the role of DNA methylation in suppressing interleukin 2 (IL-2) expression in memory CD4(+) T cells during chronic HIV-1 infection. We observed that CpG sites in the IL2 promoter of CD4(+) T cells were fully methylated in naive CD4(+) T cells and significantly demethylated in the memory populations. Interestingly, we found that the memory cells that had a terminally differentiated phenotype and expressed CD57 had increased IL2 promoter methylation relative to less differentiated memory cells in healthy individuals. Importantly, early effector memory subsets from HIV-1-infected subjects expressed high levels of CD57 and were highly methylated at the IL2 locus. Furthermore, the increased CD57 expression on memory CD4(+) T cells was inversely correlated with IL-2 production. These data suggest that DNA methylation at the IL2 locus in CD4(+) T cells is coupled to immunosenescence and plays a critical role in the broad dysfunction that occurs in polyclonal T cells during HIV-1 infection.
在慢性人类免疫缺陷病毒 1 型（HIV-1）感染期间，IL2 基因特异性失调的分子机制尚不清楚。在这里，我们研究了 DNA 甲基化在慢性 HIV-1 感染期间抑制记忆性 CD4(+) T 细胞中白细胞介素 2（IL-2）表达的作用。我们观察到，在幼稚 CD4(+) T 细胞中，IL2 启动子中的 CpG 位点完全甲基化，而在记忆性群体中则显著去甲基化。有趣的是，我们发现具有终末分化表型并表达 CD57 的记忆细胞与健康个体中分化程度较低的记忆细胞相比，IL2 启动子的甲基化程度增加。重要的是，HIV-1 感染者的早期效应记忆亚群表达高水平的 CD57 ，并且在 IL2 基因座上高度甲基化。此外，记忆性 CD4(+) T 细胞上 CD57 的表达增加与 IL-2 的产生呈负相关。这些数据表明，CD4(+) T 细胞中 IL2 基因座的 DNA 甲基化与免疫衰老有关，并在 HIV-1 感染期间多克隆 T 细胞广泛功能障碍中发挥关键作用。
