WASp-dependent actin cytoskeleton stability at the dendritic cell immunological synapse is required for extensive, functional T cell contacts.
WASp-dependent actin cytoskeleton stability at the dendritic cell immunological synapse is required for extensive, functional T cell contacts.
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DOI：
10.1189/jlb.2a0215-050rr
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发表时间：
2016-05
影响因子：
5.5
通讯作者：
Thrasher AJ
中科院分区：
文献类型：
--
作者：
Malinova D;Fritzsche M;Nowosad CR;Armer H;Munro PM;Blundell MP;Charras G;Tolar P;Bouma G;Thrasher AJ
新型 DC 足体围绕中央 MHCII 簇以稳定 IS； DC肌动蛋白细胞骨架的驱动作用。免疫突触是通信免疫细胞之间高度结构化和分子动态的界面。尽管免疫突触通过树突状细胞促进T细胞激活，但树突状细胞侧免疫突触响应T细胞参与的具体组织在很大程度上是未知的。在这项研究中，使用共聚焦和电子显微镜技术来研究树突状细胞肌动蛋白调节在免疫突触形成、稳定和功能中的作用。在树突状细胞限制性缺乏 Wiskott-Aldrich 综合征蛋白（造血细胞肌动蛋白细胞骨架的重要调节因子）的情况下，与 T 细胞的免疫突触接触占据的表面积显着减少。在分子水平上，定位于免疫突触的肌动蛋白网络表现出稳定性降低，特别是肌动蛋白相关蛋白 2/3 依赖的短丝网络。这与树突状细胞相关的 ICAM-1 和 MHC II 类极化降低有关，部分依赖于 Wiskott-Aldrich 综合征蛋白磷酸化。通过使用包含抗 ICAM-1 和抗 MHC II 类抗体的支持平面脂质双层，树突状细胞肌动蛋白细胞骨架组织成可识别的突触结构，但有趣的是，在该区域内形成了 Wiskott-Aldrich 综合征蛋白依赖性足体。这些发现表明，内在的树突状细胞细胞骨架重塑是正常免疫突触形成的关键调节成分，可能是通过粘合相互作用的巩固和免疫突触稳定性的调节来实现的。
Novel DC podosomes surround the central MHCII cluster to stabilize the IS; a driver role for the DC actin cytoskeleton. The immunological synapse is a highly structured and molecularly dynamic interface between communicating immune cells. Although the immunological synapse promotes T cell activation by dendritic cells, the specific organization of the immunological synapse on the dendritic cell side in response to T cell engagement is largely unknown. In this study, confocal and electron microscopy techniques were used to investigate the role of dendritic cell actin regulation in immunological synapse formation, stabilization, and function. In the dendritic cell-restricted absence of the Wiskott-Aldrich syndrome protein, an important regulator of the actin cytoskeleton in hematopoietic cells, the immunological synapse contact with T cells occupied a significantly reduced surface area. At a molecular level, the actin network localized to the immunological synapse exhibited reduced stability, in particular, of the actin-related protein-2/3-dependent, short-filament network. This was associated with decreased polarization of dendritic cell-associated ICAM-1 and MHC class II, which was partially dependent on Wiskott-Aldrich syndrome protein phosphorylation. With the use of supported planar lipid bilayers incorporating anti-ICAM-1 and anti-MHC class II antibodies, the dendritic cell actin cytoskeleton organized into recognizable synaptic structures but interestingly, formed Wiskott-Aldrich syndrome protein-dependent podosomes within this area. These findings demonstrate that intrinsic dendritic cell cytoskeletal remodeling is a key regulatory component of normal immunological synapse formation, likely through consolidation of adhesive interaction and modulation of immunological synapse stability.