Human cytomegalovirus drives epigenetic imprinting of the IFNG locus in [NKG2C.sup.hi] natural killer cells

• Published in: PLoS pathogens Vol. 10; no. 10
• Main Authors: Luetke-Eversloh, Merlin, Hammer, Quirin, Durek, Pawel, Nordstrom, Karl, Gasparoni, Gilles, Pink, Matthias, Hamann, Alf, Walter, Jorn, Chang, Hyun-Dong, Dong, Jun, Romagnani, Chiara
• Format: Journal Article
• Language: English
• Published: Public Library of Science 01-10-2014
• Subjects: Cell research; Cytomegaloviruses; Epigenetic inheritance; Genetic aspects; Genetic research; Health aspects; Killer cells
• ISSN: 1553-7366; 1553-7374
• DOI: 10.1371/journal.ppat.1004441

Memory type 1 T helper ([T.sub.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 [NKG2C.sup.hi] 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.sup.+] T cells or [T.sub.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.sup.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.