Abstract
Memory type 1 T helper (TH1) 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 TH1 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 NKG2Chi 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.
Highlights
In order to successfully fight infections caused by intracellular pathogens, interferon (IFN)-c is expressed during an immune response primarily by T cell lineages and natural killer (NK) cells
We identify epigenetic imprinting of the IFNG locus as selective hallmark and crucial mechanism driving strong and stable IFN-c expression in human CMV (HCMV)-specific NK cell expansions, providing a molecular basis for the regulation of adaptive features in innate cells
The specific mechanisms how HCMV might mediate ‘‘priming’’ and expansion of NKG2Chi NK cells is still not completely clear. Both NKG2C and its inhibitory counterpart CD94/NKG2A, further referred to as NKG2A, recognize the non-classical HLA class I molecule HLA-E [35,36,37], whose surface expression is stabilized by peptides derived from the leader sequence of other HLA class I molecules in a transporter associated with antigen processing (TAP)-dependent fashion [38,39]
Summary
In order to successfully fight infections caused by intracellular pathogens, interferon (IFN)-c is expressed during an immune response primarily by T cell lineages and natural killer (NK) cells. The IFNG cis-elements that show the most stringent TH1-specific hypersensitivity include the promoter and the activation-induced proximal upstream element CNS1, which is located 6 kb or 4 kb upstream of the mouse Ifng and human IFNG promoter, respectively. These regulatory regions display binding sites for T-bet, STAT4, NF-kB, and NFAT. Epigenetic analysis of the IFNG locus in total NK cells revealed an open configuration in some regions analyzed [1,9,11,12,13], the IFNG promoter undergoes partial demethylation during NK cell differentiation [14]. A more detailed analysis of additional IFNG regulatory regions in NK cell subsets is of great importance
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