title: Transcription of the activating receptor NKG2D in natural killer cells is regulated by STAT3 tyrosine phosphorylation.
abstract: Signal transducer and activator of transcription 3 (STAT3) is considered a negative regulator of inflammation, as inhibition of STAT3 signaling enhances antitumor immunity. However, STAT3 activation is a key oncogenic pathway in natural killer (NK)-lineage large granular lymphomas, and we recently reported enhanced proliferation and function of human NK cells activated with IL-21, which signals primarily through STAT3. These IL-21-expanded NK cells also have increased NKG2D expression, which led us to focus our investigation on whether STAT3 regulates NKG2D. In this study, we show that modulation of STAT3 phosphorylation with cytokines and small-molecule inhibitors correlates with NKG2D expression on human NK cells, leading to altered NK-cell degranulation. Moreover, NKG2D expression on murine NK cells having conditional STAT3 ablation is lower than on NK cells from wild-type mice, and human NK cells carrying dominant-negative STAT3 mutations have decreased baseline NKG2D expression and blunted responses to IL-10 and IL-21. Lastly, we show binding of STAT3 to a predicted STAT3 binding site upstream of the NKG2D gene, which is enhanced by IL-10 and IL-21 and decreased by STAT3 inhibition. Taken together, these data show that NKG2D expression in NK cells is regulated at the transcriptional level by STAT3, resulting in a functional NK cell defect in patients with STAT3 mutations.
authors.affiliation: Division of Pediatrics, Cell Therapy Section, and.
authors.forename: Shiguo
authors.initials: S
authors.lastname: Zhu
authors.affiliation: Division of Pediatrics, Cell Therapy Section, and.
authors.forename: Prasad V
authors.initials: PV
authors.lastname: Phatarpekar
authors.affiliation: Division of Pediatrics, Cell Therapy Section, and.
authors.forename: Cecele J
authors.initials: CJ
authors.lastname: Denman
authors.affiliation: Division of Pediatrics, Cell Therapy Section, and.
authors.forename: Vladimir V
authors.initials: VV
authors.lastname: Senyukov
authors.affiliation: Division of Pediatrics, Cell Therapy Section, and.
authors.forename: Srinivas S
authors.initials: SS
authors.lastname: Somanchi
authors.affiliation: Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, TX;
authors.forename: Hoainam T
authors.initials: HT
authors.lastname: Nguyen-Jackson
authors.affiliation: Department of Pediatrics, Section of Immunology, Allergy, and Rheumatology, Baylor College of Medicine, Houston, TX; and.
authors.forename: Emily M
authors.initials: EM
authors.lastname: Mace
authors.affiliation: Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases, Bethesda, MD.
authors.forename: Alexandra F
authors.initials: AF
authors.lastname: Freeman
authors.affiliation: Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, TX;
authors.forename: Stephanie S
authors.initials: SS
authors.lastname: Watowich
authors.affiliation: Department of Pediatrics, Section of Immunology, Allergy, and Rheumatology, Baylor College of Medicine, Houston, TX; and.
authors.forename: Jordan S
authors.identifier: http://orcid.org/0000-0001-7117-7725
authors.initials: JS
authors.lastname: Orange
authors.affiliation: Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases, Bethesda, MD.
authors.forename: Steven M
authors.initials: SM
authors.lastname: Holland
authors.affiliation: Division of Pediatrics, Cell Therapy Section, and.
authors.forename: Dean A
authors.identifier: http://orcid.org/0000-0001-6693-5392
authors.initials: DA
authors.lastname: Lee
mesh_terms: D000818:Animals; D001483:Base Sequence; D001665:Binding Sites / Q000235:genetics; D004247:DNA / Q000235:genetics / Q000378:metabolism; D006801:Humans; D016753:Interleukin-10 / Q000378:metabolism; D019409:Interleukin-15 / Q000378:metabolism; D007378:Interleukins / Q000378:metabolism; D007589:Job Syndrome / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D007694:Killer Cells, Natural / Q000276:immunology* / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D009154:Mutation; D055655:NK Cell Lectin-Like Receptor Subfamily K / Q000235:genetics*; D010766:Phosphorylation; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D014158:Transcription, Genetic; D014443:Tyrosine / Q000378:metabolism; D000098546:Interleukin-21
chemical_list: C508609:IL10 protein, human; D019409:Interleukin-15; D007378:Interleukins; C527085:KLRK1 protein, human; C527086:Klrk1 protein, mouse; D055655:NK Cell Lectin-Like Receptor Subfamily K; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; C494087:Stat3 protein, mouse; D016753:Interleukin-10; D014443:Tyrosine; D004247:DNA; D000098546:Interleukin-21