title: DNA demethylation and histone H3K9 acetylation determine the active transcription of the NKG2D gene in human CD8+ T and NK cells.
abstract: The human activating receptor NKG2D is mainly expressed by NK, NKT, γδ T and CD8(+) T cells and, under certain conditions, by CD4(+) T cells. This receptor recognizes a diverse family of ligands (MICA, MICB and ULBPs 1-6) leading to the activation of effector cells and triggering the lysis of target cells. The NKG2D receptor-ligand system plays an important role in the immune response to infections, tumors, transplanted graft and autoantigens. Elucidation of the regulatory mechanisms of NKG2D is therefore essential for therapeutic purposes. In this study, we speculate whether epigenetic mechanisms, such as DNA methylation and histone acetylation, participate in NKG2D gene regulation in T lymphocytes and NK cells. DNA methylation in the NKG2D gene was observed in CD4(+) T lymphocytes and T cell lines (Jurkat and HUT78), while this gene was unmethylated in NKG2D-positive cells (CD8(+) T lymphocytes, NK cells and NKL cell line) and associated with high levels of histone H3 lysine 9 acetylation (H3K9Ac). Treatment with the histone acetyltransferase (HAT) inhibitor curcumin reduces H3K9Ac levels in the NKG2D gene, downregulates NKG2D transcription and leads to a marked reduction in the lytic capacity of NKG2D-mediated NKL cells. These findings suggest that differential NKG2D expression in the different cell subsets is regulated by epigenetic mechanisms and that its modulation by epigenetic treatments might provide a new strategy for treating several pathologies.
authors.affiliation: Department of Immunology, Hospital Universitario Central de Asturias, Oviedo, Spain.
authors.forename: Alba
authors.initials: A
authors.lastname: Fernández-Sánchez
authors.forename: Aroa
authors.initials: A
authors.lastname: Baragaño Raneros
authors.forename: Reyes
authors.initials: R
authors.lastname: Carvajal Palao
authors.forename: Ana B
authors.initials: AB
authors.lastname: Sanz
authors.forename: Alberto
authors.initials: A
authors.lastname: Ortiz
authors.forename: Francisco
authors.initials: F
authors.lastname: Ortega
authors.forename: Beatriz
authors.initials: B
authors.lastname: Suárez-Álvarez
authors.forename: Carlos
authors.initials: C
authors.lastname: López-Larrea
mesh_terms: D000107:Acetylation / Q000187:drug effects; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects / Q000378:metabolism* / Q000502:physiology; D015550:Cell Degranulation / Q000187:drug effects / Q000235:genetics; D003474:Curcumin / Q000494:pharmacology; D003602:Cytotoxicity, Immunologic / Q000187:drug effects / Q000235:genetics; D019175:DNA Methylation / Q000187:drug effects / Q000235:genetics*; D015536:Down-Regulation / Q000187:drug effects / Q000235:genetics; D004791:Enzyme Inhibitors / Q000494:pharmacology; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology; D006657:Histones / Q000378:metabolism*; D006801:Humans; D007371:Interferon-gamma / Q000096:biosynthesis; D019169:Jurkat Cells; D007694:Killer Cells, Natural / Q000187:drug effects / Q000378:metabolism* / Q000502:physiology; D016131:Lymphocyte Subsets / Q000187:drug effects / Q000378:metabolism; D008239:Lysine / Q000378:metabolism*; D055655:NK Cell Lectin-Like Receptor Subfamily K / Q000235:genetics* / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects
chemical_list: D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; D006657:Histones; C527085:KLRK1 protein, human; D055655:NK Cell Lectin-Like Receptor Subfamily K; D007371:Interferon-gamma; D003474:Curcumin; D008239:Lysine