Subset- and tissue-defined STAT5 thresholds control homeostasis and function of innate lymphoid cells

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 STAT5 is critical for accumulation of all known ILC subsets in mice, and reveal a hierarchy of STAT5 dependency for populating lymphoid and non-lymphoid tissues. We also apply transcriptome and genomic distribution analyses to define a STAT5 gene signature in NK cells, the prototypical ILC subset, and provide a systems-based molecular rationale for its key functions downstream of IL-15. Additionally, we uncover surprising features of STAT5 behavior, most notably, the wholesale re-distribution that occurs when NK cells shift from tonic signaling to acute cytokine-driven signaling, and its genome-wide coordination with T-bet, another key transcription factor in ILC biology. Collectively, our data position STAT5 as a central node in the transcription factor network that instructs ILC development, homeostasis and function, and provide mechanistic insights on how it works at cellular and molecular levels. This dataset includes 22 individual samples of RNAseq or STAT5 ChIPseq data from ex vivo or cytokine-treated NK cells. Each culture condition includes at least 2 biological replicates per genotype.