Differential Regulation of the Let-7 Family of MicroRNAs in CD4+ T Cells Alters IL-10 Expression
Differential Regulation of the Let-7 Family of MicroRNAs in CD4+ T Cells Alters IL-10 Expression
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DOI：
10.4049/jimmunol.1101196
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发表时间：
2012-06-15
影响因子：
4.4
通讯作者：
Kelleher, Anthony D.
中科院分区：
文献类型：
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作者：
Swaminathan, Sanjay;Suzuki, Kazuo;Kelleher, Anthony D.
microRNAs（miRNAs）与22-nt小RNA相似，是mRNA周转和翻译的重要调节因子。最近的研究表明，miRNA途径在HIV-1感染中的重要性，特别是在维持潜伏期方面。我们最初的体外研究表明，与未感染的培养物相比，HIV-1感染的HUT 78细胞表达显著更高的IL-10水平。IL-10在对HIV-1的失调的细胞毒性T细胞应答中起重要作用，并且计算机模拟算法表明let-7 miRNA靶向IL-10 mRNA。在时间过程实验中，我们证明了HUT 78细胞中HIV-1感染后let-7 miRNAs迅速下降，同时IL-10也随之升高。为了显示let-7和IL-10之间的直接联系，let-7 miRNA的强制过表达导致IL-10水平显著降低，而这些miRNA的功能的抑制增加IL-10。为了证明这些结果的相关性，我们将注意力集中在未感染的健康对照、慢性HIV-1感染患者和长期无进展者的CD 4（+）T细胞上。我们表征了这三组CD 4（+）T细胞中miRNA的变化，并证明let-7 miRNA在健康对照组的CD 4（+）T细胞中高度表达，与健康对照组和长期非进展者相比，慢性HIV-1感染者的let-7 miRNA显著降低。我们描述了一种新的机制，即IL-10水平可以通过let-7 miRNAs的变化来调节。在HIV-1感染中，let-7 miRNA的减少可能导致CD 4（+）T细胞中IL-10的增加，并通过操纵宿主免疫反应为病毒提供重要的生存优势。免疫学杂志，2012，188：6238-6246。
MicroRNAs (miRNAs) are similar to 22-nt small RNAs that are important regulators of mRNA turnover and translation. Recent studies have shown the importance of the miRNA pathway in HIV-1 infection, particularly in maintaining latency. Our initial in vitro studies demonstrated that HIV-1-infected HUT78 cells expressed significantly higher IL-10 levels compared with uninfected cultures. IL-10 plays an important role in the dysregulated cytotoxic T cell response to HIV-1, and in silico algorithms suggested that let-7 miRNAs target IL10 mRNA. In a time course experiment, we demonstrated that let-7 miRNAs fall rapidly following HIV-1 infection in HUT78 cells with concomitant rises in IL-10. To show a direct link between let-7 and IL-10, forced overexpression of let-7 miRNAs resulted in significantly reduced IL-10 levels, whereas inhibition of the function of these miRNAs increased IL-10. To demonstrate the relevance of these results, we focused our attention on CD4(+) T cells from uninfected healthy controls, chronic HIV-1-infected patients, and long-term nonprogressors. We characterized miRNA changes in CD4(+) T cells from these three groups and demonstrated that let-7 miRNAs were highly expressed in CD4(+) T cells from healthy controls and let-7 miRNAs were significantly decreased in chronic HIV-1 infected compared with both healthy controls and long-term nonprogressors. We describe a novel mechanism whereby IL-10 levels can be potentially modulated by changes to let-7 miRNAs. In HIV-1 infection, the decrease in let-7 miRNAs may result in an increase in IL-10 from CD4(+) T cells and provide the virus with an important survival advantage by manipulating the host immune response. The Journal of Immunology, 2012, 188: 6238-6246.