Ly49E-dependent inhibition of natural killer cells by urokinase plasminogen activator

Tina Van Den Broeck, Frederik Stevenaert, Sylvie Taveirne, Veronique Debacker, Christel Vangestel, Bart Vandekerckhove, Tom Taghon, Patrick Matthys, Jean Plum, Werner Held, Mieke Dewerchin, Wayne M. Yokoyama, Georges Leclercq

Research output: Contribution to journalArticlepeer-review

20 Scopus citations

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-γ 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.

Original languageEnglish
Pages (from-to)5046-5051
Number of pages6
JournalBlood
Volume112
Issue number13
DOIs
StatePublished - Dec 15 2008

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