Ly49E-dependent inhibition of natural killer cells by urokinase plasminogen activator.
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.
Van Den Broeck
Tina
T
Department of Clinical Chemistry, Microbiology and Immunology, Ghent University, Ghent, Belgium.
Stevenaert
Frederik
F
Taveirne
Sylvie
S
Debacker
Veronique
V
Vangestel
Christel
C
Vandekerckhove
Bart
B
Taghon
Tom
T
Matthys
Patrick
P
Plum
Jean
J
Held
Werner
W
Dewerchin
Mieke
M
Yokoyama
Wayne M
WM
Leclercq
Georges
G
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*
D055650:NK Cell Lectin-Like Receptor Subfamily A; D007371:Interferon-gamma; D014568:Urokinase-Type Plasminogen Activator