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.

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。