title: IL-21 down-regulates NKG2D/DAP10 expression on human NK and CD8+ T cells.
abstract: IL-21 is a recently described cytokine, produced by activated Th cells, that shares significant homology with members of the IL-2 family of cytokines. IL-21 mediates its biological effects via the IL-21R in conjunction with the common receptor gamma-chain that is also shared by members of the IL-2 family. We report that culture of human primary NK and CD8+ T cells with IL-21 in combination with IL-2 results in significant reduction of the cell surface expression of NKG2D, compared with that in cells treated with IL-2 alone. The reduced expression of NKG2D after IL-21 culture had functional consequences for NK cell function, as assessed by NKG2D-mediated redirected lysis assays and degranulation assays, compared with NK cells treated with IL-2 alone. IL-21-mediated NKG2D down-regulation in human NK cells correlated with a marked reduction of DNAX-activating protein of 10 kDa (DAP10) transcription in cells treated with IL-2 in combination with IL-21 compared with cells stimulated with only IL-2. This was attributed to a dramatic reduction in DAP10 promoter activity, as assessed by a DAP10 luciferase reporter construct. In contrast to NKG2D expression, IL-21 was able to induce the expression of the NK activation receptors NKp30 and 2B4 as well as the costimulatory receptor CD28 on CD8+ T cells. These data indicate that IL-21 is able to channel NK and CD8+ T cell function by altering the expression pattern of activation/costimulatory receptors.
authors.affiliation: Receptor Cell Biology Section, Laboratory of Allergic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, MD 20852, USA.
authors.forename: Steven J
authors.initials: SJ
authors.lastname: Burgess
authors.forename: Alina I
authors.initials: AI
authors.lastname: Marusina
authors.forename: Ishani
authors.initials: I
authors.lastname: Pathmanathan
authors.forename: Francisco
authors.initials: F
authors.lastname: Borrego
authors.forename: John E
authors.initials: JE
authors.lastname: Coligan
mesh_terms: D015703:Antigens, CD / Q000096:biosynthesis / Q000235:genetics; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism*; D049109:Cell Proliferation; D002478:Cells, Cultured; D003602:Cytotoxicity, Immunologic / Q000235:genetics; D015536:Down-Regulation / Q000235:genetics / Q000276:immunology*; D017930:Genes, Reporter; D006801:Humans; D007376:Interleukin-2 / Q000494:pharmacology; D053738:Interleukin-21 Receptor alpha Subunit; D007378:Interleukins / Q000494:pharmacology*; D007694:Killer Cells, Natural / Q000276:immunology / Q000378:metabolism*; D008562:Membrane Glycoproteins / Q000096:biosynthesis / Q000235:genetics; D008565:Membrane Proteins / Q000037:antagonists & inhibitors* / Q000096:biosynthesis* / Q000235:genetics; D055655:NK Cell Lectin-Like Receptor Subfamily K; D055628:Natural Cytotoxicity Triggering Receptor 3; D010766:Phosphorylation; D011971:Receptors, Immunologic / Q000037:antagonists & inhibitors* / Q000096:biosynthesis* / Q000235:genetics; D018123:Receptors, Interleukin / Q000096:biosynthesis / Q000235:genetics; D053655:Receptors, Interleukin-21; D055607:Receptors, Natural Killer Cell; D050791:STAT Transcription Factors / Q000378:metabolism; D000071176:Signaling Lymphocytic Activation Molecule Family; D015854:Up-Regulation / Q000276:immunology; D000098546:Interleukin-21
chemical_list: D015703:Antigens, CD; C084093:CD244 protein, human; C120528:HCST protein, human; C508117:IL21R protein, human; D007376:Interleukin-2; D053738:Interleukin-21 Receptor alpha Subunit; D007378:Interleukins; C527085:KLRK1 protein, human; D008562:Membrane Glycoproteins; D008565:Membrane Proteins; C431710:NCR3 protein, human; D055655:NK Cell Lectin-Like Receptor Subfamily K; D055628:Natural Cytotoxicity Triggering Receptor 3; D011971:Receptors, Immunologic; D018123:Receptors, Interleukin; D053655:Receptors, Interleukin-21; D055607:Receptors, Natural Killer Cell; D050791:STAT Transcription Factors; D000071176:Signaling Lymphocytic Activation Molecule Family; D000098546:Interleukin-21