title: Ly49E-dependent inhibition of natural killer cells by urokinase plasminogen activator.
abstract: The Ly49 natural killer (NK)-cell receptor family comprises both activating and inhibitory members, which recognize major histocompatibility complex (MHC) class I or MHC class I-related molecules and are involved in target recognition. As previously shown, the Ly49E receptor fails to bind to a variety of soluble or cell-bound MHC class I molecules, indicating that its ligand is not an MHC class I molecule. Using BWZ.36 reporter cells, we demonstrate triggering of Ly49E by the completely distinct, non-MHC-related protein urokinase plasminogen activator (uPA). uPA is known to be secreted by a variety of cells, including epithelial and hematopoietic cells, and levels are up-regulated during tissue remodeling, infections, and tumorigenesis. Here we show that addition of uPA to Ly49E-positive adult and fetal NK cells inhibits interferon-gamma secretion and reduces their cytotoxic potential, respectively. These uPA-mediated effects are Ly49E-dependent, as they are reversed by addition of anti-Ly49E monoclonal antibody and by down-regulation of Ly49E expression using RNA interference. Our results suggest that uPA, besides its established role in fibrinolysis, tissue remodeling, and tumor metastasis, could be involved in NK cell-mediated immune surveillance and tumor escape.
authors.affiliation: Department of Clinical Chemistry, Microbiology and Immunology, Ghent University, Ghent, Belgium.
authors.forename: Tina
authors.initials: T
authors.lastname: Van Den Broeck
authors.forename: Frederik
authors.initials: F
authors.lastname: Stevenaert
authors.forename: Sylvie
authors.initials: S
authors.lastname: Taveirne
authors.forename: Veronique
authors.initials: V
authors.lastname: Debacker
authors.forename: Christel
authors.initials: C
authors.lastname: Vangestel
authors.forename: Bart
authors.initials: B
authors.lastname: Vandekerckhove
authors.forename: Tom
authors.initials: T
authors.lastname: Taghon
authors.forename: Patrick
authors.initials: P
authors.lastname: Matthys
authors.forename: Jean
authors.initials: J
authors.lastname: Plum
authors.forename: Werner
authors.initials: W
authors.lastname: Held
authors.forename: Mieke
authors.initials: M
authors.lastname: Dewerchin
authors.forename: Wayne M
authors.initials: WM
authors.lastname: Yokoyama
authors.forename: Georges
authors.initials: G
authors.lastname: Leclercq
mesh_terms: D000818:Animals; D003602:Cytotoxicity, Immunologic; D007157:Immunologic Surveillance; D007371:Interferon-gamma / Q000378:metabolism; D007694:Killer Cells, Natural / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D055650:NK Cell Lectin-Like Receptor Subfamily A / Q000502:physiology*; D019139:Tumor Escape; D014568:Urokinase-Type Plasminogen Activator / Q000502:physiology*
chemical_list: D055650:NK Cell Lectin-Like Receptor Subfamily A; D007371:Interferon-gamma; D014568:Urokinase-Type Plasminogen Activator