title: Complex regulation of human NKG2D-DAP10 cell surface expression: opposing roles of the γc cytokines and TGF-β1.
abstract: Natural killer (NK) cells help protect the host against viral infections and tumors. NKG2D is a vital activating receptor, also expressed on subsets of T cells, whose ligands are up-regulated by cells in stress. Ligation of NKG2D leads to phosphorylation of the associated DAP10 adaptor protein, thereby activating immune cells. Understanding how the expression of NKG2D-DAP10 is regulated has implications for immunotherapy. We show that IL-2 and TGF-β1 oppositely regulate NKG2D-DAP10 expression by NK cells. IL-2 stimulation increases NKG2D surface expression despite a decrease in NKG2D mRNA levels. Stimulation with IL-2 results in a small increase of DAP10 mRNA and a large up-regulation of DAP10 protein synthesis, indicating that IL-2-mediated effects are mostly posttranscriptional. Newly synthesized DAP10 undergoes glycosylation that is required for DAP10 association with NKG2D and stabilization of NKG2D expression. TGF-β1 has an opposite and dominant effect to IL-2. TGF-β1 treatment decreases DAP10, as its presence inhibits the association of RNA polymerase II with the DAP10 promoter, but not NKG2D mRNA levels. This leads to the down-regulation of DAP10 expression and, as a consequence, NKG2D protein as well. Finally, we show that other γ(c) cytokines act similarly to IL-2 in up-regulating DAP10 expression and NKG2D-DAP10 surface expression.
authors.affiliation: National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, MD, USA.
authors.forename: Yuk Pheel
authors.initials: YP
authors.lastname: Park
authors.forename: Seung-Chul
authors.initials: SC
authors.lastname: Choi
authors.forename: Patricia
authors.initials: P
authors.lastname: Kiesler
authors.forename: Aleksandra
authors.initials: A
authors.lastname: Gil-Krzewska
authors.forename: Francisco
authors.initials: F
authors.lastname: Borrego
authors.forename: Jennifer
authors.initials: J
authors.lastname: Weck
authors.forename: Konrad
authors.initials: K
authors.lastname: Krzewski
authors.forename: John E
authors.initials: JE
authors.lastname: Coligan
mesh_terms: D000954:Antigens, Surface / Q000235:genetics / Q000378:metabolism; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism*; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism / Q000494:pharmacology / Q000502:physiology*; D004336:Drug Antagonism; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D007376:Interleukin-2 / Q000494:pharmacology; D007694:Killer Cells, Natural / Q000276:immunology / Q000378:metabolism / Q000502:physiology; D055655:NK Cell Lectin-Like Receptor Subfamily K / Q000235:genetics / Q000378:metabolism*; D011401:Promoter Regions, Genetic / Q000187:drug effects; D021381:Protein Transport / Q000187:drug effects; D011971:Receptors, Immunologic / Q000235:genetics / Q000378:metabolism*; D053773:Transforming Growth Factor beta1 / Q000378:metabolism / Q000494:pharmacology / Q000502:physiology*
chemical_list: D000954:Antigens, Surface; D016207:Cytokines; C120528:HCST protein, human; D007376:Interleukin-2; D055655:NK Cell Lectin-Like Receptor Subfamily K; D011971:Receptors, Immunologic; D053773:Transforming Growth Factor beta1