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NCOR1 Orchestrates Transcriptional Landscapes and Effector Functions of CD4+ T Cells.
Frontiers in Immunology ( IF 5.7 ) Pub Date : 2020-04-03 , DOI: 10.3389/fimmu.2020.00579
Daniela Hainberger 1 , Valentina Stolz 1 , Ci Zhu 2 , Michael Schuster 3 , Lena Müller 1 , Patricia Hamminger 1 , Ramona Rica 1 , Darina Waltenberger 1 , Marlis Alteneder 1 , Thomas Krausgruber 3 , Anastasiya Hladik 4 , Sylvia Knapp 3, 4 , Christoph Bock 3, 5 , Michael Trauner 2 , Michael A Farrar 6 , Wilfried Ellmeier 1
Affiliation  

The differentiation of naïve CD4+ T cells into T helper (Th) subsets is key for a functional immune response and has to be tightly controlled by transcriptional and epigenetic processes. However, the function of cofactors that connect gene-specific transcription factors with repressive chromatin-modifying enzymes in Th cells is yet unknown. Here we demonstrate an essential role for nuclear receptor corepressor 1 (NCOR1) in regulating naïve CD4+ T cell and Th1/Th17 effector transcriptomes. Moreover, NCOR1 binds to a conserved cis-regulatory element within the Ifng locus and controls the extent of IFNγ expression in Th1 cells. Further, NCOR1 controls the survival of activated CD4+ T cells and Th1 cells in vitro, while Th17 cell survival was not affected in the absence of NCOR1. In vivo, effector functions were compromised since adoptive transfer of NCOR1-deficient CD4+ T cells resulted in attenuated colitis due to lower frequencies of IFNγ+ and IFNγ+IL-17A+ Th cells and overall reduced CD4+ T cell numbers. Collectively, our data demonstrate that the coregulator NCOR1 shapes transcriptional landscapes in CD4+ T cells and controls Th1/Th17 effector functions.

中文翻译:


NCOR1 协调 CD4+ T 细胞的转录景观和效应器功能。



幼稚 CD4+ T 细胞分化为辅助性 T (Th) 亚群是功能性免疫反应的关键,并且必须受到转录和表观遗传过程的严格控制。然而,Th 细胞中将基因特异性转录因子与抑制性染色质修饰酶连接起来的辅助因子的功能尚不清楚。在这里,我们证明了核受体辅阻遏物 1 (NCOR1) 在调节幼稚 CD4+ T 细胞和 Th1/Th17 效应转录组中的重要作用。此外,NCOR1 与 Ifng 基因座内的保守顺式调节元件结合,并控制 Th1 细胞中 IFNγ 表达的程度。此外,NCOR1 在体外控制激活的 CD4+ T 细胞和 Th1 细胞的存活,而在缺乏 NCOR1 的情况下 Th17 细胞的存活不受影响。在体内,由于 IFNγ+ 和 IFNγ+IL-17A+ Th 细胞频率较低以及 CD4+ T 细胞数量总体减少,NCOR1 缺陷型 CD4+ T 细胞的过继转移导致结肠炎减弱,因此效应器功能受到损害。总的来说,我们的数据表明,核心调节器 NCOR1 塑造 CD4+ T 细胞中的转录景观并控制 Th1/Th17 效应器功能。
更新日期:2020-04-06
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