Transcriptional regulation of FOXP3 requires integrated activation of both promoter and CNS regions in tumor-induced CD8(+) Treg cells.
Transcriptional regulation of FOXP3 requires integrated activation of both promoter and CNS regions in tumor-induced CD8(+) Treg cells.
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DOI：
10.1038/s41598-017-01788-z
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发表时间：
2017-05-09
影响因子：
4.6
通讯作者：
Sa G
中科院分区：
文献类型：
--
作者：
Chakraborty S;Panda AK;Bose S;Roy D;Kajal K;Guha D;Sa G
调节性T细胞是肿瘤微环境中的一个高潮，并诱导免疫逃避。CD 4 + Treg细胞已得到很好的表征，而CD 8 + Treg细胞在癌症中的作用最近开始引起关注。在这里，我们报告了乳腺肿瘤微环境中CD 8 + FOXP 3 + T细胞的增加。FOXP 3是谱系特异性转录因子，是Treg细胞发育和功能的主要调节因子。FOXP 3优先由CD 4 + Treg细胞中的趋异信号传导诱导。但是FOXP 3在肿瘤-CD 8 + T细胞中是如何被诱导和维持的，这是研究的灰姑娘。我们观察到，RUNX 3，一个CD 8+谱系特异性转录因子，结合在FOXP 3-启动子，以诱导其转录。除了启动子激活，参与的顺式元件CNS 1和CNS 2的转录调控FOXP 3在这些细胞中也很明显。SMAD 3与CNS 1区域结合并作为转录诱导物，而GATA 3通过CNS区域中的差异染色质修饰在FOXP 3转录中起时间作用。在CNS 1区，GATA 3在幼稚CD 8 + T细胞中作为FOXP 3的阻遏物。而在CD 8 + T细胞中，GATA 3直接结合在CNS 2区域，并促使FOXP 3的维持。因此，这些协同转录机制的干预可能在癌症的免疫治疗中具有治疗潜力。
T-regulatory cells are an upsurge in the tumor microenvironment and induce immune-evasion. CD4+ Treg cells are well characterized whereas the role of CD8+ Tregs in cancer has recently started to crease attention. Here, we report an augmentation CD8+FOXP3+ Tregs in breast tumor microenvironment. FOXP3, the lineage-specific transcription factor, is a dominant regulator of Treg cell development and function. FOXP3 is induced preferentially by divergent signaling in CD4+ Treg cells. But how FOXP3 is induced and maintained in tumor-CD8+ Tregs is the Cinderella of the investigation. We observed that RUNX3, a CD8+ lineage-specific transcription factor, binds at the FOXP3-promoter to induce its transcription. In addition to promoter activation, involvement of cis-elements CNS1 and CNS2 in the transcriptional regulation of FOXP3 was also evident in these cells. SMAD3 binds to CNS1 region and acts as transcription inducer, whereas GATA3 plays a temporal role in the FOXP3 transcription by differential chromatin modification in CNS regions. In CNS1 region, GATA3 acts as a repressor for FOXP3 in naïve CD8+ T cells. Whereas in CD8+ Tregs, GATA3 binds directly at CNS2 region and persuaded the maintenance of FOXP3. Therefore, the intervention of these concerted transcriptional machinery may have a therapeutic potential in immunotherapy of cancer.