Deconvoluting global cytokine signaling networks in natural killer cells

Nat Immunol. 2021 May;22(5):627-638. doi: 10.1038/s41590-021-00909-1. Epub 2021 Apr 15.


Cytokine signaling via signal transducer and activator of transcription (STAT) proteins is crucial for optimal antiviral responses of natural killer (NK) cells. However, the pleiotropic effects of both cytokine and STAT signaling preclude the ability to precisely attribute molecular changes to specific cytokine-STAT modules. Here, we employed a multi-omics approach to deconstruct and rebuild the complex interaction of multiple cytokine signaling pathways in NK cells. Proinflammatory cytokines and homeostatic cytokines formed a cooperative axis to commonly regulate global gene expression and to further repress expression induced by type I interferon signaling. These cytokines mediated distinct modes of epigenetic regulation via STAT proteins, and collective signaling best recapitulated global antiviral responses. The most dynamically responsive genes were conserved across humans and mice, which included a cytokine-STAT-induced cross-regulatory program. Thus, an intricate crosstalk exists between cytokine signaling pathways, which governs NK cell responses.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Separation
  • Chromatin Immunoprecipitation Sequencing
  • Disease Models, Animal
  • Epigenesis, Genetic / immunology*
  • Female
  • Flow Cytometry
  • Gene Regulatory Networks / immunology
  • Herpesviridae Infections / blood
  • Herpesviridae Infections / immunology*
  • Herpesviridae Infections / virology
  • Humans
  • Immunity, Innate / genetics
  • Interleukins / metabolism*
  • Killer Cells, Natural / immunology*
  • Killer Cells, Natural / metabolism
  • Male
  • Mice
  • Mice, Knockout
  • Muromegalovirus / immunology
  • Principal Component Analysis
  • RNA-Seq
  • STAT Transcription Factors / genetics
  • STAT Transcription Factors / metabolism*
  • Signal Transduction / genetics
  • Signal Transduction / immunology


  • Interleukins
  • STAT Transcription Factors