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

Alejandro V. Villarino, Giuseppe Sciumè, Fred P. Davis, Shigeru Iwata, Beatrice Zitti, Gertraud W. Robinson, Lothar Hennighausen, Yuka Kanno, John J. O'Shea

Research output: Contribution to journalArticlepeer-review

53 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)2999-3104
Number of pages106
JournalJournal of Experimental Medicine
Volume214
Issue number10
DOIs
StatePublished - 2017
Externally publishedYes

ASJC Scopus subject areas

  • Medicine(all)

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