CD28-stimulated ERK2 phosphorylation is required for polarization of the microtubule organizing center and granules in YTS NK cells
CD28-stimulated ERK2 phosphorylation is required for polarization of the microtubule organizing center and granules in YTS NK cells
复制标题
DOI：
10.1073/pnas.0604236103
复制
发表时间：
2006-07-05
影响因子：
11.1
通讯作者：
Strominger, Jack L.
中科院分区：
文献类型：
--
作者：
Chen, Xi;Allan, David S. J.;Strominger, Jack L.
自然杀伤（NK）细胞毒性的激活需要与易感靶细胞粘附并形成缀合物，随后是肌动蛋白聚合，以及微管组织中心（MTOC）和溶细胞颗粒向NK细胞免疫突触的极化。在此，通过使用YTS NK细胞系作为模型，CD 28显示为活化受体。它在依赖于磷酸肌醇-3激酶激活的过程中发出细胞毒性信号，导致持续的细胞外信号调节激酶2（ERK 2）磷酸化。ERK和磷酸化ERK定位于微管丝。无论是与靶点的结合还是肌动蛋白聚合都不受阻断ERK 2活化的影响。然而，通过阻断ERK 2活化，MTOC和溶细胞颗粒向突触区域的极化以及NK细胞的细胞毒性均强烈降低。还确定了CD 28/CD 80相互作用在人外周NK细胞的细胞毒性中的作用。相比之下，淋巴细胞功能相关抗原1（LFA-1）连接仅转导瞬时ERK 2激活，不能诱导YTS细胞的杀伤。因此，在YTS细胞中，通过刺激持续的ERK 2活化，CD 28信号用于将MTOC和溶细胞颗粒转移到NK细胞免疫突触。
Activation of natural killer (NK) cell cytotoxicity requires adhesion and formation of a conjugate with a susceptible target cell, followed by actin polymerization, and polarization of the microtubule organizing center (MTOC) and cytolytic granules to the NK cell immune synapse. Here, by using the YTS NK cell line as a model, CD28 is shown to be an activating receptor. It signals cytotoxicity in a process dependent on phosphoinositide-3 kinase activation, leading to sustained extracellular signal-regulated kinase 2 (ERK2) phosphorylation. ERK and phospho-ERK localize to microtubule filaments. Neither conjugation with targets nor actin polymerization is affected by blocking ERK2 activation. However, both polarization of the MTOC and cytolytic granules to the synaptic region and NK cell cytotoxicity are strongly reduced by blocking ERK2 activation. A role for the CD28/CD80 interaction in cytotoxicity of human peripheral NK cells also was established. By contrast, lymphocyte function-associated antigen 1 (LFA-1) ligation transduces only a transient ERK2 activation and fails to induce killing in YTS cells. Thus, in YTS cells, a CD28 signal is used to polarize the MTOC and cytolytic granules to the NK cell immune synapse by stimulating sustained ERK2 activation.