Subset- and tissue-defined STAT5 thresholds control homeostasis and function of innate lymphoid cells.
Alejandro V VillarinoGiuseppe SciumèFred P DavisShigeru IwataBeatrice ZittiGertraud W RobinsonLothar HennighausenYuka KannoJohn J O'SheaPublished in: The Journal of experimental medicine (2017)
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.
Keyphrases
- nk cells
- genome wide
- cell proliferation
- induced apoptosis
- copy number
- transcription factor
- dna methylation
- gene expression
- type diabetes
- liver failure
- metabolic syndrome
- endoplasmic reticulum stress
- oxidative stress
- climate change
- skeletal muscle
- high fat diet induced
- electronic health record
- acute respiratory distress syndrome
- rna seq
- dna binding
- deep learning
- network analysis