title: Gene deregulation and chronic activation in natural killer cells deficient in the transcription factor ETS1.
abstract: Multiple transcription factors guide the development of mature functional natural killer (NK) cells, yet little is known about their function. We used global gene expression and genome-wide binding analyses combined with developmental and functional studies to unveil three roles for the ETS1 transcription factor in NK cells. ETS1 functions at the earliest stages of NK cell development to promote expression of critical transcriptional regulators including T-BET and ID2, NK cell receptors (NKRs) including NKp46, Ly49H, and Ly49D, and signaling molecules essential for NKR function. As a consequence, Ets1(-/-) NK cells fail to degranulate after stimulation through activating NKRs. Nonetheless, these cells are hyperresponsive to cytokines and have characteristics of chronic stimulation including increased expression of inhibitory NKRs and multiple activation-associated genes. Therefore, ETS1 regulates a broad gene expression program in NK cells that promotes target cell recognition while limiting cytokine-driven activation.
authors.affiliation: Committee on Immunology, The University of Chicago, Chicago, IL 60615, USA.
authors.forename: Kevin
authors.initials: K
authors.lastname: Ramirez
authors.forename: Katherine J
authors.initials: KJ
authors.lastname: Chandler
authors.forename: Christina
authors.initials: C
authors.lastname: Spaulding
authors.forename: Sasan
authors.initials: S
authors.lastname: Zandi
authors.forename: Mikael
authors.initials: M
authors.lastname: Sigvardsson
authors.forename: Barbara J
authors.initials: BJ
authors.lastname: Graves
authors.forename: Barbara L
authors.initials: BL
authors.lastname: Kee
mesh_terms: D020816:Amino Acid Motifs; D000818:Animals; D001665:Binding Sites; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D002478:Cells, Cultured / Q000187:drug effects / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects / Q000276:immunology; D051797:Inhibitor of Differentiation Protein 2 / Q000096:biosynthesis / Q000235:genetics; D019409:Interleukin-15 / Q000494:pharmacology / Q000502:physiology; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics; D007694:Killer Cells, Natural / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D008213:Lymphocyte Activation / Q000187:drug effects / Q000235:genetics / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D050784:Proto-Oncogene Protein c-ets-1 / Q000172:deficiency* / Q000235:genetics / Q000502:physiology; D011828:Radiation Chimera; D055607:Receptors, Natural Killer Cell / Q000096:biosynthesis / Q000235:genetics; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology; D020825:T-Box Domain Proteins / Q000096:biosynthesis / Q000235:genetics; D014157:Transcription Factors / Q000096:biosynthesis / Q000235:genetics; D014158:Transcription, Genetic / Q000187:drug effects / Q000276:immunology; D000098815:T-bet Transcription Factor
chemical_list: C494042:Ets1 protein, mouse; C497452:Idb2 protein, mouse; D051797:Inhibitor of Differentiation Protein 2; D019409:Interleukin-15; D047908:Intracellular Signaling Peptides and Proteins; D050784:Proto-Oncogene Protein c-ets-1; D055607:Receptors, Natural Killer Cell; D020825:T-Box Domain Proteins; D000098815:T-bet Transcription Factor; D014157:Transcription Factors