Human cytomegalovirus drives epigenetic imprinting of the IFNG locus in NKG2Chi natural killer cells

PLoS Pathog. 2014 Oct 16;10(10):e1004441. doi: 10.1371/journal.ppat.1004441. eCollection 2014 Oct.


Memory type 1 T helper (T(H)1) cells are characterized by the stable expression of interferon (IFN)-γ as well as by the epigenetic imprinting of the IFNG locus. Among innate cells, NK cells play a crucial role in the defense against cytomegalovirus (CMV) and represent the main source of IFN-γ. Recently, it was shown that memory-like features can be observed in NK cell subsets after CMV infection. However, the molecular mechanisms underlying NK cell adaptive properties have not been completely defined. In the present study, we demonstrated that only NKG2Chi NK cells expanded in human CMV (HCMV) seropositive individuals underwent epigenetic remodeling of the IFNG conserved non-coding sequence (CNS) 1, similar to memory CD8(+) T cells or T(H)1 cells. The accessibility of the CNS1 was required to enhance IFN-γ transcriptional activity in response to NKG2C and 2B4 engagement, which led to consistent IFN-γ production in NKG2C(hi) NK cells. Thus, our data identify epigenetic imprinting of the IFNG locus as selective hallmark and crucial mechanism driving strong and stable IFN-γ expression in HCMV-specific NK cell expansions, providing a molecular basis for the regulation of adaptive features in innate cells.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • CD56 Antigen / immunology
  • CD8-Positive T-Lymphocytes / immunology*
  • Cell Differentiation / immunology
  • Cytomegalovirus / genetics*
  • Cytomegalovirus Infections / genetics*
  • Epigenesis, Genetic* / genetics
  • Epigenesis, Genetic* / immunology
  • Genetic Loci
  • Humans
  • Interferon-gamma / genetics*
  • Killer Cells, Natural / immunology
  • NK Cell Lectin-Like Receptor Subfamily C / genetics
  • NK Cell Lectin-Like Receptor Subfamily C / metabolism*


  • CD56 Antigen
  • KLRC2 protein, human
  • NK Cell Lectin-Like Receptor Subfamily C
  • Interferon-gamma

Grants and funding

This work was supported by the Deutsche Forschungsgemeinschaft (DFG) SFB 650 and SFB 633. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.