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

作者：Alejandro V. Villarino, Giuseppe Sciumè, Fred P. Davis, S. Iwata, Béatrice Zitti, Gertraud W. Robinson, Lothar Hennighausen, Yuka Kanno, John J. O’Shea · 发表于：The Journal of Experimental Medicine · 年份：2017 · DOI：10.1084/jem.20150907 · 被引用次数：97 · 研究领域：IL-33, ST2, and ILC Pathways、Immune Cell Function and Interaction、Eosinophilic Esophagitis

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.