Department of Immunology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
Proc Natl Acad Sci U S A. 2010 Jun 29;107(26):11912-7. doi: 10.1073/pnas.0913422107. Epub 2010 Jun 14.
Cytolytic effectors polarize toward target cells for effective killing and IFN-gamma secretion. The spatiotemporal features of this polarization and their importance for cytolysis have not been resolved. In cytotoxic T cells and natural killer (NK) cells, transient polarization was consistently associated with effective killing. Polarization was regulated by Cdc42, a small Rho family GTPase universally critical for cytoskeletal dynamics. Transient accumulation of active Cdc42 at the cytolytic effector/target cell interface and focus of such accumulation on the interface center were closely related to cytolysis. Surprisingly, however, the intensity of Cdc42 activation was not. We interfered with Cdc42 activation in NK cells such that sustained polarization in long lasting nonkilling cell couples was selectively blocked. Thus the proportion of the NK cell population displaying transient polarization was increased. As a consequence, cytolytic responder frequency and IFN-gamma production were enhanced upon such interference with Cdc42 activation. These data support the notion that transience in polarization is critical for cytolytic effector function, likely by preventing cytolytic effectors from becoming trapped in nonproductive target cell interactions.
细胞毒性效应器向靶细胞极化以进行有效杀伤和 IFN-γ 分泌。这种极化的时空特征及其对细胞杀伤的重要性尚未得到解决。在细胞毒性 T 细胞和自然杀伤 (NK) 细胞中，短暂的极化与有效杀伤始终相关。极化受 Cdc42 调节，Cdc42 是一种普遍对细胞骨架动力学至关重要的小 Rho 家族 GTP 酶。细胞毒性效应器/靶细胞界面处活性 Cdc42 的短暂积累及其在界面中心的此类积累焦点与细胞杀伤密切相关。然而，令人惊讶的是，Cdc42 的激活强度并非如此。我们在 NK 细胞中干扰 Cdc42 的激活，从而选择性地阻止在持续时间较长的非杀伤性细胞对中持续极化。因此，显示短暂极化的 NK 细胞群体的比例增加。因此，通过这种干扰 Cdc42 的激活，细胞毒性应答者的频率和 IFN-γ 的产生得到增强。这些数据支持这样一种观点，即极化的短暂性对于细胞毒性效应器功能至关重要，可能是通过防止细胞毒性效应器陷入非生产性靶细胞相互作用中。
