title: Education of hyporesponsive NK cells by cytokines.
abstract: NK-cell tolerance to self is mediated via engagement of inhibitory receptors by cognate MHC molecules. This event is critical for NK-cell education to achieve functional competence. Thus, NK cells expressing self-MHC-specific inhibitory receptors are responsive to activating stimuli while those lacking such receptors are hyporesponsive. Nevertheless, the mechanisms underlying NK-cell education are still poorly understood. Here, we show that after stimulation with cytokines, hyporesponsive NK cells acquire stable expression of killer Ig-like receptors (KIR) as reflected by DNA hypomethylation of their KIR locus. Remarkably, only hyporesponsive NK cells that acquire KIR in the presence of their cognate MHC molecule gain functional competence and this process can occur in the absence of any accessory cells. Acquisition of competence does not result in autoreactivity, since acquired KIR are functional and therefore able to inhibit NK-cell cytotoxicity. Our data demonstrate that competent NK cells can be generated by cytokine stimulation, suggesting that NK-cell education might not only be an early event which takes place during NK-cell development but might also occur in the periphery during an immune response.
authors.affiliation: German Rheumatism Research Center, DRFZ, Berlin, Germany.
authors.forename: Kerstin
authors.initials: K
authors.lastname: Juelke
authors.forename: Monica
authors.initials: M
authors.lastname: Killig
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: D018899:CpG Islands; D016207:Cytokines / Q000276:immunology* / Q000494:pharmacology; D003602:Cytotoxicity, Immunologic / Q000235:genetics*; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D006801:Humans; D007113:Immunity, Innate / Q000235:genetics; D007694:Killer Cells, Natural / Q000187:drug effects / Q000276:immunology*; D052118:Lysosomal-Associated Membrane Protein 1 / Q000276:immunology; D055654:NK Cell Lectin-Like Receptor Subfamily C / Q000096:biosynthesis / Q000235:genetics; D011401:Promoter Regions, Genetic; D054340:Receptors, KIR / Q000096:biosynthesis / Q000235:genetics; D054341:Receptors, KIR3DL1 / Q000096:biosynthesis / Q000235:genetics
chemical_list: D016207:Cytokines; C515083:KIR3DL1 protein, human; D052118:Lysosomal-Associated Membrane Protein 1; D055654:NK Cell Lectin-Like Receptor Subfamily C; D054340:Receptors, KIR; D054341:Receptors, KIR3DL1