YY1 inhibits differentiation and function of regulatory T cells by blocking Foxp3 expression and activity.
YY1 inhibits differentiation and function of regulatory T cells by blocking Foxp3 expression and activity.
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DOI：
10.1038/ncomms10789
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发表时间：
2016-02-19
影响因子：
16.6
通讯作者：
Lee GR
中科院分区：
文献类型：
--
作者：
Hwang SS;Jang SW;Kim MK;Kim LK;Kim BS;Kim HS;Kim K;Lee W;Flavell RA;Lee GR
调节性T（Treg）细胞对于维持免疫稳态是必不可少的。Foxp 3是Treg细胞分化和功能的关键转录因子;然而，对其负调控的分子机制知之甚少。在这里，我们表明，YY 1的表达是较低的Treg细胞比Tconv细胞，其过表达导致Foxp 3的表达和Treg细胞的抑制功能的废除显着减少。在硫酸葡聚糖诱导的结肠炎模型中，在炎症条件下Treg细胞中YY 1增加，同时抑制活性降低。YY 1抑制Smad 3/4与Foxp 3基因座的结合和染色质重塑。此外，YY 1通过与Foxp 3物理相互作用和直接结合Foxp 3靶基因来中断Foxp 3依赖性靶基因表达。因此，YY 1通过阻断Foxp 3抑制Treg细胞的分化和功能。 Treg控制免疫反应的大小，但这些细胞是如何被控制的还不太清楚。在这里，作者表明，转录抑制因子YY 1通过抑制Treg的主调节因子Foxp 3的转录，并通过与Foxp 3及其靶基因启动子直接相互作用来抑制Foxp 3。
Regulatory T (Treg) cells are essential for maintenance of immune homeostasis. Foxp3 is the key transcription factor for Treg-cell differentiation and function; however, molecular mechanisms for its negative regulation are poorly understood. Here we show that YY1 expression is lower in Treg cells than Tconv cells, and its overexpression causes a marked reduction of Foxp3 expression and abrogation of suppressive function of Treg cells. YY1 is increased in Treg cells under inflammatory conditions with concomitant decrease of suppressor activity in dextran sulfate-induced colitis model. YY1 inhibits Smad3/4 binding to and chromatin remodelling of the Foxp3 locus. In addition, YY1 interrupts Foxp3-dependent target gene expression by physically interacting with Foxp3 and by directly binding to the Foxp3 target genes. Thus, YY1 inhibits differentiation and function of Treg cells by blocking Foxp3. Treg control the magnitude of immune responses, but how these cells are controlled is less understood. Here the authors show that a transcriptional repressor YY1 inhibits Foxp3, the master regulator of Treg, by repressing its transcription, and by directly interacting with Foxp3 and its target gene promoters.