Tethering of intercellular adhesion molecule on target cells is required for LFA-1-dependent NK cell adhesion and granule polarization.
Tethering of intercellular adhesion molecule on target cells is required for LFA-1-dependent NK cell adhesion and granule polarization.
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DOI：
10.4049/jimmunol.1000761
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发表时间：
2010-09-01
期刊：
影响因子：
--
通讯作者：
Long EO
中科院分区：
文献类型：
--
作者：
Gross CC;Brzostowski JA;Liu D;Long EO
αLβ2整合素（αLβ2 integrin，LFA-1）在T细胞和NK细胞的细胞毒性免疫突触形成和靶细胞杀伤中具有重要作用。LFA-1与靶细胞上的ICAM结合不仅促进NK细胞中的粘附，而且促进溶细胞颗粒的极化。在这里，我们测试了LFA-1依赖性NK细胞反应是否受靶细胞表面ICAM的分布和移动性的调节。我们发现，在NK敏感的靶细胞中，F-肌动蛋白的解聚消除了原代NK细胞中LFA-1依赖的缀合物形成和颗粒极化。不受LFA-1控制的脱粒没有受损。光漂白实验后的荧光恢复和颗粒跟踪全内反射荧光显微镜显示，ICAM-1和ICAM-2分布在很大程度上不动的集群。细胞间粘附分子簇在肌动蛋白解聚后保持高度移动的。此外，通过表达ezrin（一种将蛋白质束缚在肌动蛋白细胞骨架上的衔接分子）降低NK抗性靶细胞上的ICAM-2迁移率，增强了LFA-1依赖性粘附和颗粒极化。最后，当NK细胞在脂双层上的可自由扩散的ICAM-1上移动时，它们在固相ICAM-1上结合并扩散。我们的结论是，系留，而不是聚集的ICAM促进适当的信号转导LFA-1在NK细胞。我们的研究结果表明，细胞上的整合素配体的侧向扩散可能是细胞毒性淋巴细胞裂解的易感性的一个重要决定因素。
αLβ2 integrin (LFA-1) has an important role in the formation of T cell and NK cell cytotoxic immunological synapses and in target cell killing. Binding of LFA-1 to ICAM on target cells promotes not only adhesion, but also polarization of cytolytic granules in NK cells. Here we tested whether LFA-1-dependent NK cell responses are regulated by the distribution and mobility of ICAM at the surface of target cells. We show that depolymerization of F-actin in NK-sensitive target cells abrogated LFA-1-dependent conjugate formation and granule polarization in primary NK cells. Degranulation, which is not controlled by LFA-1, was not impaired. Fluorescence recovery after photobleaching experiments and particle tracking by total internal reflection fluorescence microscopy revealed that ICAM-1 and ICAM-2 were distributed in largely immobile clusters. ICAM clusters were maintained and became highly mobile after actin depolymerization. Moreover, reducing ICAM-2 mobility on an NK-resistant target cell through expression of ezrin, an adapter molecule that tethers proteins to the actin cytoskeleton, enhanced LFA-1-dependent adhesion and granule polarization. Finally, while NK cells kept moving over freely diffusible ICAM-1 on a lipid bilayer, they bound and spread over solid-phase ICAM-1. We conclude that tethering, rather than clustering of ICAM promotes proper signaling by LFA-1 in NK cells. Our findings suggest that the lateral diffusion of integrin ligands on cells may be an important determinant of susceptibility to lysis by cytotoxic lymphocytes.
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DOI：
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发表时间：
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期刊：
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影响因子：
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