Galandrini R, De Maria R, Piccoli M, Frati L, Santoni A
Department of Experimental Medicine, La Sapienza, University of Rome, Italy.
J Immunol. 1994 Nov 15;153(10):4399-407.
CD44, a major hyaluronate receptor, is involved in a variety of lymphocyte functions including lympho-hemopoiesis, adhesion to high endothelial venules or the extracellular matrix, and T cell activation. Here we investigated the ability of CD44 to affect the cytotoxic functions of human NK cells. Ligation of CD44 by selected mAb (J173 and F10442) resulted in a rapid, dose-response-dependent enhancement of NK cytotoxic activity against a panel of tumor target cells that varied in their sensitivity to NK killing. Neither enhanced killing against NK-resistant target cells nor CD44 mAb-mediated redirected lysis was not observed. CD44 cross-linking also was found to up-regulate CD16-mediated lysis. In an attempt to investigate the early biochemical events that occur after CD44 ligation, we found that optimal cross-linking conditions induce a rapid increase of intracellular free calcium levels, which is abrogated by extracellular Ca2+ chelation. Moreover, enhanced and more sustained Ca2+ rise resulted from CD16 and CD44 coengagement. In contrast, no inositol 1,4,5-trisphosphate generation was found after optimal CD44 cross-linking. These results suggest that although CD44 is not capable of delivering a lytic signal in human NK cells, it coactivates spontaneous or CD16-mediated NK cytotoxicity. The variation in intracellular free calcium may be one of the signals that account for the costimulation of the lytic activity.
CD44是一种主要的透明质酸受体，参与多种淋巴细胞功能，包括淋巴细胞造血、与高内皮微静脉或细胞外基质的黏附以及T细胞活化。在此，我们研究了CD44影响人类自然杀伤（NK）细胞细胞毒性功能的能力。用选定的单克隆抗体（J173和F10442）连接CD44，导致针对一组对NK杀伤敏感性不同的肿瘤靶细胞的NK细胞毒性活性迅速增强，且呈剂量反应依赖性。未观察到对NK抗性靶细胞的杀伤增强，也未观察到CD44单克隆抗体介导的重定向裂解。还发现CD44交联可上调CD16介导的裂解。为了研究CD44连接后发生的早期生化事件，我们发现最佳交联条件会导致细胞内游离钙水平迅速升高，而细胞外Ca2+螯合可消除这种升高。此外，CD16和CD44共同参与会导致Ca2+升高增强且更持久。相比之下，最佳CD44交联后未发现肌醇1,4,5 -三磷酸生成。这些结果表明，虽然CD44在人类NK细胞中不能传递裂解信号，但它可共同激活自发或CD16介导的NK细胞毒性。细胞内游离钙的变化可能是解释裂解活性共刺激的信号之一。
