Phospholipase C-γ2 is essential for NK cell cytotoxicity and innate immunity to malignant and virally infected cells
Phospholipase C-γ2 is essential for NK cell cytotoxicity and innate immunity to malignant and virally infected cells
复制标题
DOI：
10.1182/blood-2005-06-2428
复制
发表时间：
2006-02-01
期刊：
影响因子：
20.3
通讯作者：
Colucci, F
中科院分区：
文献类型：
--
作者：
Caraux, A;Kim, N;Colucci, F
磷脂酶C-γ 2（PLC-γ 2）是白细胞中信号转导的关键组分。在自然杀伤（NK）细胞中，PLC-γ 2是细胞毒性的关键;然而，尚不清楚它调节细胞溶解机制的哪些步骤。我们发现，PLC-γ 2-缺陷型NK细胞与靶细胞形成缀合物，并极化微管组织中心，但由于钙动员缺陷，未能分泌细胞毒性颗粒。因此，在PLC-γ 2缺陷细胞中，细胞毒性完全消除，无论靶点是否表达NKG 2D配体，缺失自身主要组织相容性复合体（MHC）1类，或者NK细胞是否用IL-2和NKR-P1 C、CD 16、CD 244、Ly 49 D和Ly 49 H特异性抗体刺激。分泌缺陷是细胞毒性颗粒特异性的，因为IL-12刺激时IFN-γ的释放是正常的。Plcg 2（-/-）小鼠不能排斥MHC I类缺陷型淋巴瘤细胞，也不能控制CMV感染，但它们有效地抑制了单核细胞增生李斯特菌感染。我们的研究结果表明，胞吐的细胞毒性颗粒，而不是细胞极化的目标，取决于细胞内钙离子的上升，在NK细胞的细胞毒性。在体内，PLC-γ 2调节先天免疫的选择性方面，因为它对于NK细胞对恶性和病毒感染细胞的应答而不是对细菌感染的应答是必需的。
Phospholipase C-gamma 2 (PLC-gamma 2) is a key component of signal transduction in leukocytes. In natural killer (NK) cells, PLC-gamma 2 is pivotal for cellular cytotoxicity; however, it is not known which steps of the cytolytic machinery it regulates. We found that PLC-gamma 2-deficient NK cells formed conjugates with target cells and polarized the microtubule-organizing center, but failed to secrete cytotoxic granules, due to defective calcium mobilization. Consequently, cytotoxicity was completely abrogated in PLC-gamma 2-deficient cells, regardless of whether targets expressed NKG2D ligands, missed self major histocompatibility complex (MHC) class 1, or whether NK cells were stimulated with IL-2 and antibodies specific for NKR-P1C, CD16, CD244, Ly49D, and Ly49H. Defective secretion was specific to cytotoxic granules because release of IFN-gamma on stimulation with IL-12 was normal. Plcg2(-/-) mice could not reject MHC class I-deficient lymphoma cells nor could they control CMV infection, but they effectively contained Listeria monocytogenes infection. Our results suggest that exocytosis of cytotoxic granules, but not cellular polarization toward targets, depends on intracellular calcium rise during NK cell cytotoxicity. In vivo, PLC-gamma 2 regulates selective facets of innate immunity because it is essential for NK cell responses to malignant and virally infected cells but not to bacterial infections.