Inserm, Unité U768, Laboratoire du Développement Normal et Pathologique du Système Immunitaire, Paris, France.
Inserm, Institut Fédératif de Recherche Necker Enfants-Malades (IFR94), Université Paris Descartes, Paris, France.
Blood. 2012 Apr 26;119(17):3879-89. doi: 10.1182/blood-2011-09-382556. Epub 2012 Feb 3.
Cytotoxic T lymphocytes kill target cells via the polarized secretion of cytotoxic granules at the immune synapse. The lytic granules are initially recruited around the polarized microtubule-organizing center. In a dynein-dependent transport process, the granules move along microtubules toward the microtubule-organizing center in the minus-end direction. Here, we found that a kinesin-1-dependent process is required for terminal transport and secretion of polarized lytic granule to the immune synapse. We show that synaptotagmin-like protein 3 (Slp3) is an effector of Rab27a in cytotoxic T lymphocytes and interacts with kinesin-1 through the tetratricopeptide repeat of the kinesin-1 light chain. Inhibition of the Rab27a/Slp3/kinesin-1 transport complex impairs lytic granule secretion. Our data provide further molecular insights into the key functional and regulatory mechanisms underlying the terminal transport of cytotoxic granules and the latter's secretion at the immune synapse.
细胞毒性 T 淋巴细胞通过在免疫突触处极化分泌细胞毒性颗粒来杀死靶细胞。溶酶体颗粒最初在极化微管组织中心周围被募集。在依赖动力蛋白的运输过程中，颗粒沿着微管向微管组织中心的负端方向移动。在这里，我们发现，一个依赖驱动蛋白-1 的过程对于极化溶酶体颗粒向免疫突触的末端运输和分泌是必需的。我们表明，突触结合蛋白样蛋白 3（Slp3）是细胞毒性 T 淋巴细胞中 Rab27a 的效应蛋白，通过驱动蛋白-1 轻链的四肽重复与驱动蛋白-1 相互作用。Rab27a/Slp3/驱动蛋白-1 运输复合物的抑制会损害溶酶体颗粒的分泌。我们的数据为细胞毒性颗粒末端运输和在免疫突触处分泌的关键功能和调节机制提供了进一步的分子见解。
