title: NK cells gain higher IFN-γ competence during terminal differentiation.
abstract: NK cells are the main cells of the innate immune system that produce IFN-γ, and they express this cytokine at early stages of maturation in response to cytokine stimulation. Conversely, acquisition of IFN-γ-competence in CD4(+) T helper cells requires a differentiation process from naïve toward type 1 (Th1) cells, which is associated with epigenetic remodeling at the IFNG locus. In the present study, we show that the ability of NK cells to produce IFN-γ in response to activating receptor (actR) engagement is gradually acquired during terminal differentiation and is accompanied by progressively higher NF-κB activation in response to actR triggering. Moreover, during the differentiation process NK cells gradually display increasing expression of IFNG and TBX21 (encoding T-bet) transcripts and demethylation at the IFNG promoter. This study provides new insights in the molecular mechanisms underlying NK-cell ability to express IFN-γ upon actR engagement. Thus, we propose that in order to efficiently produce IFN-γ in response to infected or transformed cells, NK cells gain Th1-like features, such as higher IFN-γ competence and epigenetic remodeling of the IFNG promoter, during their terminal differentiation.
authors.affiliation: Innate Immunity, Deutsches Rheuma-Forschungszentrum, A Leibniz Institute, Berlin, Germany.
authors.forename: Merlin
authors.initials: M
authors.lastname: Luetke-Eversloh
authors.forename: Basak B
authors.initials: BB
authors.lastname: Cicek
authors.forename: Francesco
authors.initials: F
authors.lastname: Siracusa
authors.forename: Jenny T
authors.initials: JT
authors.lastname: Thom
authors.forename: Alf
authors.initials: A
authors.lastname: Hamann
authors.forename: Stefan
authors.initials: S
authors.lastname: Frischbutter
authors.forename: Ria
authors.initials: R
authors.lastname: Baumgrass
authors.forename: Hyun-Dong
authors.initials: HD
authors.lastname: Chang
authors.forename: Andreas
authors.initials: A
authors.lastname: Thiel
authors.forename: Jun
authors.initials: J
authors.lastname: Dong
authors.forename: Chiara
authors.initials: C
authors.lastname: Romagnani
mesh_terms: D002454:Cell Differentiation; D018899:CpG Islands; D019175:DNA Methylation; D006801:Humans; D007371:Interferon-gamma / Q000096:biosynthesis* / Q000235:genetics; D007694:Killer Cells, Natural / Q000166:cytology / Q000276:immunology*; D016328:NF-kappa B / Q000502:physiology; D055655:NK Cell Lectin-Like Receptor Subfamily K / Q000502:physiology; D055627:Natural Cytotoxicity Triggering Receptor 1 / Q000502:physiology; D055628:Natural Cytotoxicity Triggering Receptor 3 / Q000502:physiology; D011401:Promoter Regions, Genetic; D020825:T-Box Domain Proteins / Q000502:physiology; D000098815:T-bet Transcription Factor
chemical_list: C527085:KLRK1 protein, human; C112260:NCR1 protein, human; C431710:NCR3 protein, human; D016328:NF-kappa B; D055655:NK Cell Lectin-Like Receptor Subfamily K; D055627:Natural Cytotoxicity Triggering Receptor 1; D055628:Natural Cytotoxicity Triggering Receptor 3; D020825:T-Box Domain Proteins; D000098815:T-bet Transcription Factor; D007371:Interferon-gamma
keywords: Cell differentiation; Chromatin remodeling; IFN-γ; NK cells