Cutting Edge: STAT1-Mediated Epigenetic Control of Rsad2 Promotes Clonal Expansion of Antiviral NK Cells

J Immunol. 2020 Jul 1;205(1):21-25. doi: 10.4049/jimmunol.2000086. Epub 2020 May 27.


NK cells represent a cellular component of innate immunity but possess features of adaptive immunity, including clonal expansion and establishment of long-lived memory following infection. During mouse CMV (MCMV) infection, we observed Rsad2 (which encodes Viperin) to be among the most highly induced IFN stimulatory genes in activated NK cells, correlating with increased chromatin accessibility at the Rsad2 gene locus. Furthermore, in NK cells stimulated with IFN-α, the promoter region of Rsad2 was enriched for STAT1 binding and the permissive histone mark H3K4me3. IFN-αR- and STAT1-deficient NK cells showed an impairment of Rsad2 induction and chromatin accessibility during MCMV infection. Finally, Rsad2-deficient NK cells were defective in clonal expansion and memory formation following exposure to MCMV, in part because of greater apoptosis. Thus, our study reveals a critical mechanism of STAT1-mediated epigenetic control of Rsad2 to promote the adaptive behavior of NK cells during viral infection.

Publication types

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

MeSH terms

  • Animals
  • Cell Differentiation / genetics
  • Cells, Cultured
  • Chromatin Immunoprecipitation Sequencing
  • Disease Models, Animal
  • Epigenesis, Genetic / immunology*
  • Herpesviridae Infections / immunology*
  • Herpesviridae Infections / virology
  • Histone Code / genetics
  • Humans
  • Immunity, Cellular / genetics
  • Immunity, Innate / genetics
  • Immunologic Memory / genetics
  • Interferon-alpha / immunology
  • Interferon-alpha / metabolism
  • Killer Cells, Natural / immunology*
  • Killer Cells, Natural / metabolism
  • Lymphocyte Activation / genetics
  • Mice
  • Mice, Knockout
  • Muromegalovirus / immunology
  • Primary Cell Culture
  • Promoter Regions, Genetic / genetics
  • Proteins / genetics*
  • STAT1 Transcription Factor / metabolism*


  • Interferon-alpha
  • Proteins
  • Rsad2 protein, mouse
  • STAT1 Transcription Factor
  • Stat1 protein, mouse