Marcenaro Emanuela, Augugliaro Raffaella, Falco Michela, Castriconi Roberta, Parolini Silvia, Sivori Simona, Romeo Elisa, Millo Romano, Moretta Lorenzo, Bottino Cristina, Moretta Alessandro
Dipartimento di Medicina Sperimentale, Università degli Studi di Genova, Genova, Italy.
Eur J Immunol. 2003 Dec;33(12):3367-76. doi: 10.1002/eji.200324425.
Triggering of cytotoxicity in human NK cells is induced by the combined engagement of several triggering receptors. These include primary receptors such as NKG2D and the natural cytotoxicity receptors (NCR) NKp30, NKp46 and NKp44, while other molecules, including 2B4, NTB-A and NKp80, function as co-receptors. As reported in the present study, during an attempt to identify novel NK receptors or co-receptors, we found that CD59 functions as a co-receptor in human NK cell activation; engagement of CD59 by specific mAb delivers triggering signals to human NK cells, resulting in enhancement of cytotoxicity. Similar to other NK co-receptors, the triggering function of CD59, a glycosylphosphatidylinositol (GPI)-linked protein, depends on the simultaneous engagement of primary receptors such as NCR. Accordingly, CD59-dependent triggering was virtually restricted to NK cells expressing high surface densities of NKp46, and mAb-mediated modulation of NKp46 resulted in markedly decreased responses to anti-CD59 mAb. Biochemical analysis revealed that CD59 is physically associated with NKp46 and NKp30. Moreover, engagement of CD59 resulted in tyrosine phosphorylation of CD3zeta chains associated with these NCR, but not those associated with CD16. Thus, CD59-mediated costimulation of NK cells requires direct physical interaction of this GPI-linked protein with primary triggering NK receptors.
几种触发受体的联合作用可诱导人自然杀伤（NK）细胞的细胞毒性。这些受体包括主要受体，如NKG2D和自然细胞毒性受体（NCR）NKp30、NKp46和NKp44，而其他分子，包括2B4、NTB - A和NKp80，则作为共受体发挥作用。如本研究报道，在试图鉴定新型NK受体或共受体的过程中，我们发现CD59在人NK细胞激活中作为共受体发挥作用；特异性单克隆抗体（mAb）与CD59结合可向人NK细胞传递触发信号，从而增强细胞毒性。与其他NK共受体类似，糖基磷脂酰肌醇（GPI）连接蛋白CD59的触发功能取决于NCR等主要受体的同时结合。因此，CD59依赖性触发实际上仅限于高表达表面NKp46的NK细胞，mAb介导的NKp46调节导致对抗CD59 mAb的反应显著降低。生化分析表明，CD59与NKp46和NKp30存在物理关联。此外，CD59的结合导致与这些NCR相关的CD3ζ链发生酪氨酸磷酸化，但与CD16相关的CD3ζ链未发生磷酸化。因此，CD59介导的NK细胞共刺激需要这种GPI连接蛋白与主要触发NK受体直接发生物理相互作用。
