title: Membrane-type 6 matrix metalloproteinase regulates the activation-induced downmodulation of CD16 in human primary NK cells.
abstract: CD16 (FcγRIIIa), the low-affinity receptor for IgG, expressed by the majority of human NK cells, is a potent activating receptor that facilitates Ab-dependent cell-mediated cytotoxicity (ADCC). ADCC dysfunction has been linked to cancer progression and poor prognosis for chronic infections, such as HIV; thus, understanding how CD16 expression is regulated by NK cells has clinical relevance. Importantly, CD16 cell-surface expression is downmodulated following NK cell activation and, in particular, exposure to stimulatory cytokines (IL-2 or IL-15), likely owing to the action of matrix metalloproteinases (MMPs). In this article, we identify membrane-type 6 (MT6) MMP (also known as MMP25) as a proteinase responsible for CD16 downmodulation. IL-2-induced upregulation of MT6/MMP25 cell-surface expression correlates with CD16 downmodulation. MT6/MMP25, sequestered in intracellular compartments in unstimulated NK cells, translocates to the cell surface after stimulation; moreover, it polarizes to the effector-target cell interface of the CD16-mediated immunological synapse. siRNA-mediated disruption of MT6/MMP25 expression enhances the ADCC capacity of NK cells, emphasizing the important functional role of MT6/MMP25 in the regulation of ADCC activity. Thus, this study uncovers a previously unknown role of MT6/MMP25 in human NK cells, and suggests that inhibition of MT6/MMP25 activity could improve ADCC efficacy of therapeutically administered NK cells that require IL-2 for culture and expansion.
authors.affiliation: Receptor Cell Biology Section, Laboratory of Immunogenetics, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, MD 20852, USA.
authors.forename: Giovanna
authors.initials: G
authors.lastname: Peruzzi
authors.forename: Laurette
authors.initials: L
authors.lastname: Femnou
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: D000920:Antibody-Dependent Cell Cytotoxicity / Q000187:drug effects; D002450:Cell Communication; D002451:Cell Compartmentation; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000378:metabolism; D016764:Cell Polarity; D002478:Cells, Cultured; D004151:Dipeptides / Q000494:pharmacology; D015536:Down-Regulation / Q000187:drug effects; D004705:Endocytosis / Q000187:drug effects; D058851:GPI-Linked Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology; D005786:Gene Expression Regulation / Q000187:drug effects / Q000276:immunology; D006801:Humans; D054992:Immunological Synapses; D019409:Interleukin-15 / Q000494:pharmacology; D007376:Interleukin-2 / Q000494:pharmacology*; D007694:Killer Cells, Natural / Q000187:drug effects / Q000276:immunology / Q000378:metabolism* / Q000648:ultrastructure; D008213:Lymphocyte Activation / Q000187:drug effects; D053504:Matrix Metalloproteinases, Membrane-Associated / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D021381:Protein Transport; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000494:pharmacology; D017452:Receptors, IgG / Q000096:biosynthesis* / Q000235:genetics; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D014158:Transcription, Genetic / Q000187:drug effects
chemical_list: D004151:Dipeptides; C428200:FCGR3B protein, human; D058851:GPI-Linked Proteins; D019409:Interleukin-15; D007376:Interleukin-2; C078131:N-(2(R)-2-(hydroxamidocarbonylmethyl)-4-methylpentanoyl)-L-tryptophan methylamide; D034741:RNA, Small Interfering; D017452:Receptors, IgG; D011993:Recombinant Fusion Proteins; D053504:Matrix Metalloproteinases, Membrane-Associated; C403928:matrix metalloproteinase 25; D013755:Tetradecanoylphorbol Acetate