The transcription factor Zfp281 sustains CD4+ T lymphocyte activation through directly repressing Ctla-4 transcription
The transcription factor Zfp281 sustains CD4+ T lymphocyte activation through directly repressing Ctla-4 transcription
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转录因子 Zfp281 通过直接抑制 Ctla-4 转录来维持 CD4 T 淋巴细胞活化。
DOI：
10.1038/s41423-019-0289-y
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发表时间：
2020-12-01
影响因子：
24.1
通讯作者：
Wang, Lie
中科院分区：
文献类型：
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作者：
Guo, Jing;Xue, Zhonghui;Wang, Lie
共抑制受体（如CTLA-4）在效应T细胞上的表达是负调控T细胞活化的关键机制。然而，CTLA-4的转录调控尚不清楚。Zfp281是一种C2H2锌指蛋白，是胚胎干细胞多能性维持的负调控因子。然而，Zfp281在分化细胞中的功能尚未被研究。我们制造了Zfp281条件敲除小鼠，其中Zfp281基因的功能被Cd4（Cre）转基因条件破坏，以研究其对T细胞功能的影响。Zfp281对T细胞的发育没有影响，但由于T细胞受体信号的减弱，CD4(+) T细胞的活化和细胞因子的产生受到损害。此外，Zfp281缺陷抑制了体内T细胞对单核增生李斯特菌感染的反应。通过全基因组表达谱分析，我们确定Zfp281通过直接结合其启动子中富含gc的位点来抑制Ctla-4的表达，从而抑制T细胞激活的负反馈。与此结果一致，CTLA-4阻断和shRNA敲低部分挽救了由Zfp281缺陷引起的细胞因子产生减少。这些发现表明Zfp281通过直接抑制Ctla-4转录来维持CD4(+) T淋巴细胞的激活。
The expression of coinhibitory receptors, such as CTLA-4, on effector T cells is a key mechanism for the negative regulation of T-cell activation. However, the transcriptional regulation of CTLA-4 is not well understood. Zfp281, a C2H2 zinc finger protein, is a negative regulator of pluripotency maintenance of embryonic stem cells. Nevertheless, the function of Zfp281 in differentiated cells has not been studied. We generated Zfp281 conditional knockout mice in which the function of the Zfp281 gene was conditionally disrupted by the Cd4(Cre) transgene to study its impact on T cell function. Zfp281 had no effect on T-cell development, but CD4(+) T cell activation and cytokine production were impaired due to diminished T-cell receptor signaling. Furthermore, Zfp281 deficiency inhibited in vivo T cell responses to Listeria monocytogenes infection. Using genome-wide expression profiling assays, we determined that Zfp281 repressed Ctla-4 expression by directly binding to GC-rich sites in its promoter, which inhibited the negative feedback of T cell activation. In line with this result, CTLA-4 blockade and shRNA knockdown partly rescued the reduced cytokine production caused by Zfp281 deficiency. These findings indicate that Zfp281 sustains CD4(+) T lymphocyte activation by directly repressing Ctla-4 transcription.