Van Den Broeck Tina, Stevenaert Frederik, Taveirne Sylvie, Debacker Veronique, Vangestel Christel, Vandekerckhove Bart, Taghon Tom, Matthys Patrick, Plum Jean, Held Werner, Dewerchin Mieke, Yokoyama Wayne M, Leclercq Georges
Department of Clinical Chemistry, Microbiology and Immunology, Ghent University, Ghent, Belgium.
Blood. 2008 Dec 15;112(13):5046-51. doi: 10.1182/blood-2008-06-164350. Epub 2008 Sep 10.
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.
Ly49自然杀伤（NK）细胞受体家族包括激活型和抑制型成员，它们识别主要组织相容性复合体（MHC）I类分子或MHC I类相关分子，并参与靶细胞识别。如先前所示，Ly49E受体无法与多种可溶性或细胞结合的MHC I类分子结合，这表明其配体不是MHC I类分子。利用BWZ.36报告细胞，我们证明了完全不同的、与MHC无关的蛋白尿激酶型纤溶酶原激活剂（uPA）可触发Ly49E。已知uPA由多种细胞分泌，包括上皮细胞和造血细胞，并且在组织重塑、感染和肿瘤发生过程中其水平会上调。在此我们表明，将uPA添加到Ly49E阳性的成年和胎儿NK细胞中，分别会抑制γ干扰素分泌并降低其细胞毒性潜能。这些uPA介导的效应依赖于Ly49E，因为添加抗Ly49E单克隆抗体以及使用RNA干扰下调Ly49E表达可使其逆转。我们的结果表明，uPA除了在纤维蛋白溶解、组织重塑和肿瘤转移中已确定的作用外，还可能参与NK细胞介导的免疫监视和肿瘤逃逸。
