Cluster size regulates protein sorting in the immunological synapse
Cluster size regulates protein sorting in the immunological synapse
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DOI：
10.1073/pnas.0902621106
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发表时间：
2009-08-04
影响因子：
11.1
通讯作者：
Groves, Jay T.
中科院分区：
文献类型：
--
作者：
Hartman, Nina C.;Nye, Jeffrey A.;Groves, Jay T.
在T细胞识别抗原的过程中，T细胞上的信号分子与抗原提呈细胞上的配体结合，并组织成空间上不同的模式。这些统称为免疫突触(IS)。大尺度空间组织和信号转导之间的因果关系此前已经建立起来。尽管已知IS形成过程中的受体运输是由肌动蛋白聚合驱动的，但不同蛋白质在空间上排序的机制仍不清楚。这些分选过程有助于信号调节的一个方面；因此，它们的阐明对于最终了解通过T细胞受体的信号转导是重要的。在这里，我们使用混合活T细胞支持的膜系统来研究蛋白质簇大小作为分选机制。共刺激分子淋巴细胞功能相关抗原-1(LFA-1)的聚集状态是通过直接抗体交联或通过将其细胞间黏附分子-1配体交联在支撑的双层上来调节的。在成熟的IS中，天然的LFA-1通常定位于中央T细胞受体簇周围的外周环内。任何一种方法诱导的LFA-1聚集度越高，都会导致逐渐更加集中的局部化，最聚集的物种完全重新定位到中心区。这些结果表明，簇的大小直接影响蛋白质在T细胞IS中的空间定位。我们讨论了一种基于与肌动蛋白细胞骨架的摩擦耦合的分选机制，该机制与这些观察结果一致，原则上可以扩展到突触中的所有细胞表面蛋白。
During antigen recognition by T cells, signaling molecules on the T cell engage ligands on the antigen-presenting cell and organize into spatially distinctive patterns. These are collectively known as the immunological synapse (IS). Causal relationships between large-scale spatial organization and signal transduction have previously been established. Although it is known that receptor transport during IS formation is driven by actin polymerization, the mechanisms by which different proteins become spatially sorted remain unclear. These sorting processes contribute a facet of signal regulation; thus their elucidation is important for ultimately understanding signal transduction through the T cell receptor. Here we investigate protein cluster size as a sorting mechanism using the hybrid live T cell-supported membrane system. The clustering state of the co-stimulatory molecule lymphocyte function-associated antigen-1 (LFA-1) is modulated, either by direct antibody crosslinking or by crosslinking its intercellular adhesion molecule-1 ligand on the supported bilayer. In a mature IS, native LFA-1 generally localizes into a peripheral ring surrounding a central T cell receptor cluster. Higher degrees of LFA-1 clustering, induced by either method, result in progressively more central localization, with the most clustered species fully relocated to the central zone. These results demonstrate that cluster size directly influences protein spatial positioning in the T cell IS. We discuss a sorting mechanism, based on frictional coupling to the actin cytoskeleton, that is consistent with these observations and is, in principle, extendable to all cell surface proteins in the synapse.