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

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

Author information

1
Innate Immunity, Deutsches Rheuma-Forschungszentrum - A Leibniz Institute, Berlin, Germany.
2
Experimental Rheumatology, Deutsches Rheuma-Forschungszentrum - A Leibniz Institute, Berlin, Germany; Cell Biology, Deutsches Rheuma-Forschungszentrum - A Leibniz Institute, Berlin, Germany.
3
Department of Genetics, University of Saarland, Saarbrücken, Germany.
4
Experimental Rheumatology, Deutsches Rheuma-Forschungszentrum - A Leibniz Institute, Berlin, Germany.
5
Cell Biology, Deutsches Rheuma-Forschungszentrum - A Leibniz Institute, Berlin, Germany.

Abstract

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.

PMID:
25329659
PMCID:
PMC4199780
DOI:
10.1371/journal.ppat.1004441
[Indexed for MEDLINE]
Free PMC Article

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