An initial and rapid step of lytic granule secretion precedes microtubule organizing center polarization at the cytotoxic T lymphocyte/target cell synapse
An initial and rapid step of lytic granule secretion precedes microtubule organizing center polarization at the cytotoxic T lymphocyte/target cell synapse
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DOI：
10.1073/pnas.1218640110
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发表时间：
2013-04-09
影响因子：
11.1
通讯作者：
Valitutti, Salvatore
中科院分区：
文献类型：
--
作者：
Bertrand, Florie;Mueller, Sabina;Valitutti, Salvatore
目前的假设是，细胞毒性T淋巴细胞（ctl）的致命攻击递送与中心体向靶细胞的极化机制有关，导致在有限的分泌域内专门释放溶解颗粒。在这里，我们提供了三条证据，表明这种机制可能不适用于致命打击交付的一般范例。首先，在固定化多肽MHC复合物刺激的ctl中，通过全内反射荧光显微镜检测到，溶解颗粒和微管组织中心定位到突触区域的时空解离。其次，在许多CTL/靶细胞偶联物中，溶解颗粒分泌先于微管极化，可以在细胞接触后的第一分钟内检测到。第三，抑制微管组织中心和中心体极化既不影响CTL突触裂解颗粒的释放，也不影响杀伤效率。我们的研究结果揭示了裂解颗粒分泌的极快步骤，并表明微管组织中心极化对于有效的致命打击递送是必不可少的，从而拓宽了目前对CTL生物学的看法。
It is presently assumed that lethal hit delivery by cytotoxic T lymphocytes (CTLs) is mechanistically linked to centrosome polarization toward target cells, leading to dedicated release of lytic granules within a confined secretory domain. Here we provide three lines of evidence showing that this mechanism might not apply as a general paradigm for lethal hit delivery. First, in CTLs stimulated with immobilized peptide MHC complexes, lytic granules and microtubule organizing center localization into synaptic areas are spatio-temporally dissociated, as detected by total internal reflection fluorescence microscopy. Second, in many CTL/target cell conjugates, lytic granule secretion precedes microtubule polarization and can be detected during the first minute after cell cell contact. Third, inhibition of microtubule organizing center and centrosome polarization impairs neither lytic granule release at the CTL synapse nor killing efficiency. Our results broaden current views of CTL biology by revealing an extremely rapid step of lytic granule secretion and by showing that microtubule organizing center polarization is dispensable for efficient lethal hit delivery.