Zemmour David, Pratama Alvin, Loughhead Scott M, Mathis Diane, Benoist Christophe
Division of Immunology, Department of Microbiology and Immunobiology, Harvard Medical School, Boston, MA 02115.
Division of Immunology, Department of Microbiology and Immunobiology, Harvard Medical School, Boston, MA 02115
Proc Natl Acad Sci U S A. 2017 Apr 25;114(17):E3472-E3480. doi: 10.1073/pnas.1700946114. Epub 2017 Apr 10.
A combination of transcription factors, enhancers, and epigenetic marks determines the expression of the key transcription factor FoxP3 in regulatory T cells (Tregs). Adding an additional layer of complexity, the long noncoding RNA (lncRNA) ( long intergenic noncoding RNA) is a negative regulator that tunes expression, resulting in a subset of Tregs with twofold- to fivefold-lower levels of FoxP3 protein. The impact of is particularly marked in conditions of IL-2 deficiency, and, conversely, IL-2 represses expression. neighbors in mouse and human genomes, is specifically expressed in mature Tregs, and acts only in It does not affect DNA methylation, but modifies chromatin accessibility in the conserved noncoding sequence 3 (CNS3)/Accessible region 5 (AR5) region of Like many lncRNAs, 's molecular effects are subtle, but by curtailing Treg activity, markedly promotes autoimmune diabetes and, conversely, restrains antiviral responses. This mechanism of FoxP3 control may allow escape from dominant Treg control during infection or cancer, at the cost of heightened autoimmunity.
转录因子、增强子和表观遗传标记的组合决定了调节性T细胞（Tregs）中关键转录因子FoxP3的表达。更复杂的是，长链非编码RNA（lncRNA）（长基因间非编码RNA）是一种负调节因子，可调节其表达，导致一部分Tregs中FoxP3蛋白水平降低两到五倍。在白细胞介素-2（IL-2）缺乏的情况下，其影响尤为显著，相反，IL-2会抑制其表达。在小鼠和人类基因组中与相邻，在成熟Tregs中特异性表达，且仅在其中起作用。它不影响DNA甲基化，但会改变在保守非编码序列3（CNS3）/可及区域5（AR5）区域的染色质可及性。与许多lncRNA一样，的分子效应很微妙，但通过减少Treg活性，会显著促进自身免疫性糖尿病，相反，会抑制抗病毒反应。这种FoxP3的调控机制可能会在感染或癌症期间以自身免疫增强为代价，使机体逃脱占主导地位的Treg控制。
