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

• Published in: The Journal of experimental medicine Vol. 214; no. 10; pp. 2999 - 3014
• Main Authors: Villarino, Alejandro V, Sciumè, Giuseppe, Davis, Fred P, Iwata, Shigeru, Zitti, Beatrice, Robinson, Gertraud W, Hennighausen, Lothar, Kanno, Yuka, O'Shea, John J
• Format: Journal Article
• Language: English
• Published: United States Rockefeller University Press 02.10.2017; The Rockefeller University Press
• Subjects: Accumulation; Animal tissues; Animals; Flow Cytometry; Gene expression; Gene Expression Profiling; Genomes; Homeostasis; Homeostasis - physiology; Immunity, Cellular - physiology; Immunity, Innate - physiology; Interfaces; Interleukin 15; Killer Cells, Natural - metabolism; Killer Cells, Natural - physiology; Lymphocytes - physiology; Lymphoid cells; Mice; Mice, Inbred C57BL; Mice, Knockout; Natural killer cells; Signaling; Stat5 protein; STAT5 Transcription Factor - genetics; STAT5 Transcription Factor - physiology; Transcription factors
• ISSN: 0022-1007; 1540-9538
• DOI: 10.1084/jem.20150907

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.