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 (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. This is a work of the U.S. Government and is not subject to copyright protection in the United States. Foreign copyrights may apply.

Citation

Alejandro V Villarino, Giuseppe Sciumè, Fred P Davis, Shigeru Iwata, Beatrice Zitti, Gertraud W Robinson, Lothar Hennighausen, Yuka Kanno, John J O'Shea. Subset- and tissue-defined STAT5 thresholds control homeostasis and function of innate lymphoid cells. The Journal of experimental medicine. 2017 Oct 02;214(10):2999-3014

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PMID: 28916644

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