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 hi...

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Bibliographic Details
Published in:The Journal of experimental medicine 2017-10, Vol.214 (10), p.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: Article
Language:English
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
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Summary: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.
ISSN:0022-1007
1540-9538
DOI:10.1084/jem.20150907