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Subset- and tissue-defined STAT5 thresholds control homeostasis and function of innate lymphoid cells
Journal of Experimental Medicine ( IF 12.6 ) Pub Date : 2017-09-15 , DOI: 10.1084/jem.20150907
Alejandro V. Villarino 1 , Giuseppe Sciumè 1 , Fred P. Davis 1 , Shigeru Iwata 1 , Beatrice Zitti 1 , Gertraud W. Robinson 2 , Lothar Hennighausen 2 , Yuka Kanno 1 , John J. O’Shea 1
Affiliation  

Innate lymphoid cells (ILCs) patrol environmental interfaces to defend against infection and protect barrier integrity. Using a genetic tuning model, we demonstrate that the signal-dependent transcription factor (TF) STAT5 is critical for accumulation of all known ILC subsets in mice and reveal a hierarchy of STAT5 dependency for populating lymphoid and nonlymphoid tissues. We apply transcriptome and genomic distribution analyses to define a STAT5 gene signature in natural killer (NK) cells, the prototypical ILC subset, and provide a systems-based molecular rationale for its key functions downstream of IL-15. We also uncover surprising features of STAT5 behavior, most notably the wholesale redistribution that occurs when NK cells shift from tonic signaling to acute cytokine-driven signaling, and genome-wide coordination with T-bet, another key TF in ILC biology. Collectively, our data position STAT5 as a central node in the TF network that instructs ILC development, homeostasis, and function and provide mechanistic insights on how it works at cellular and molecular levels.



中文翻译:

亚组和组织定义的STAT5阈值控制先天淋巴样细胞的稳态和功能

先天性淋巴样细胞(ILC)巡逻环境界面以防御感染并保护屏障完整性。使用遗传调整模型,我们证明了信号依赖性转录因子(TF)STAT5对于小鼠中所有已知ILC子集的积累至关重要,并揭示了STAT5依赖性的淋巴组织和非淋巴组织的层次结构。我们应用转录组和基因组分布分析来定义自然杀手(NK)细胞(典型的ILC子集)中的STAT5基因标记,并为其在IL-15下游的关键功能提供基于系统的分子原理。我们还发现了STAT5行为的令人惊讶的特征,最值得注意的是,当NK细胞从强直信号转为急性细胞因子驱动的信号,以及与T-bet的全基因组协调时,发生了批发再分配,ILC生物学中的另一个关键TF。总而言之,我们的数据位置STAT5作为TF网络中的中心节点,可指导ILC的发展,体内平衡和功能,并提供有关其在细胞和分子水平上的工作原理的机械见解。

更新日期:2017-09-15
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