Altered NKG2D function in NK cells induced by chronic exposure to NKG2D ligand-expressing tumor cells
Altered NKG2D function in NK cells induced by chronic exposure to NKG2D ligand-expressing tumor cells
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DOI：
10.1182/blood-2005-03-0918
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发表时间：
2005-09-01
期刊：
影响因子：
20.3
通讯作者：
Held, W
中科院分区：
文献类型：
--
作者：
Coudert, JD;Zimmer, J;Held, W
NKG2D是一种激活受体，允许自然杀伤(NK)细胞检测患病的宿主细胞。NKG2D与相应配体的结合导致受体的表面调制，并在随后的受体结合时功能减弱。然而，目前还不清楚除了调节外，NKG2D受体复合体和/或其信号转导能力是否被保留。我们在这里表明，与肿瘤细胞结合但不是可溶的配体的长期接触可以完全使NKG2D受体从细胞内钙动员和细胞介导的细胞溶解作用中解脱出来。然而，由于NKG2D配体暴露的NK细胞可以通过Ly49D受体激活，因此细胞溶解效应功能是完整的。虽然NKG2D依赖的细胞毒性受到损害，但长期的配体暴露会导致结构性干扰素伽马(干扰素伽马)的产生，这表明信号持续。这些功能变化与相关信号转导接头10 kDa的DNAX激活蛋白(DAP-10)和12 kDa的杀伤细胞激活受体相关蛋白/DNAX激活蛋白(Karap/DAP-12)的表达减少有关。这可能是结构性NKG2D参与和信号传递的结果，因为当刺激肿瘤细胞被移除时，NKG2D的功能和接头表达恢复到正常。因此，慢性暴露于表达NKG2D配体的肿瘤细胞会改变NKG2D信号，并可能促进肿瘤细胞逃避NK细胞的反应。
NKG2D is an activation receptor that allows natural killer (NK) cells to detect diseased host cells. The engagement of NKG2D with corresponding ligand results in surface modulation of the receptor and reduced function upon subsequent receptor engagement. However, it is not clear whether in addition to modulation the NKG2D receptor complex and/or its signaling capacity is preserved. We show here that the prolonged encounter with tumor cell-bound, but not soluble, ligand can completely uncouple the NKG2D receptor from the intracellular mobilization of calcium and the exertion of cell-mediated cytolysis. However, cytolytic effector function is intact since NKG2D ligand-exposed NK cells can be activated via the Ly49D receptor. While NKG2D-dependent cytotoxicity is impaired, prolonged ligand exposure results in constitutive interferon gamma (IFN gamma) production, suggesting sustained signaling. The functional changes are associated with a reduced presence of the relevant signal transducing adaptors DNAX-activating protein of 10 kDa (DAP-10) and killer cell activating receptor-associated protein/DNAX-activating protein of 12 kDa (KARAP/DAP-12). That is likely the consequence of constitutive NKG2D engagement and signaling, since NKG2D function and adaptor expression is restored to normal when the stimulating tumor cells are removed. Thus, the chronic exposure to tumor cells expressing NKG2D ligand alters NKG2D signaling and may facilitate the evasion of tumor cells from NK cell reactions.