Cytoskeletal remodeling mediated by WASp in dendritic cells is necessary for normal immune synapse formation and T-cell priming
Cytoskeletal remodeling mediated by WASp in dendritic cells is necessary for normal immune synapse formation and T-cell priming
复制标题
DOI：
10.1182/blood-2011-03-340265
复制
发表时间：
2011-09-01
期刊：
影响因子：
20.3
通讯作者：
Thrasher, Adrian J.
中科院分区：
文献类型：
--
作者：
Bouma, Gerben;Mendoza-Naranjo, Ariadna;Thrasher, Adrian J.
T细胞中细胞骨架的重排在免疫突触(IS)这一复杂的信号接口的组织中起着关键作用。令人惊讶的是，抗原提呈细胞，特别是树突状细胞(DC)对IS的结构和功能的贡献还没有得到详细的研究。我们使用了Wiskott-Aldrich综合征蛋白(WASP)缺乏导致的细胞骨架功能障碍的自然模型，以探讨DC细胞骨架在IS形成和T细胞启动中的作用。在抗原特异性系统中，当DC单独缺乏黄蜂时，T-DC接触不稳定，并与IS结构的多个缺陷相关。其结果是，DC不能支持正常的IL-12分泌，TCR信号下游的事件被取消，包括钙流量增加，微管组织中心(MTOC)极化，ZAP-70磷酸化和T细胞增殖。因此，有效信号接口的形成依赖于DC中活跃的细胞骨架重排，即使在T细胞功能正常的情况下也是如此。DC介导的活性缺乏可能是AS患者以及异基因造血干细胞移植后髓系重建有限的患者观察到的不同免疫失调的重要原因。(血。2011；118(9)：2492-2501)
Rearrangement of the cytoskeleton in T cells plays a critical role in the organization of a complex signaling interface referred to as immunologic synapse (IS). Surprisingly, the contribution of antigen presenting cells, in particular dendritic cells (DCs), to the structure and function of the IS has not been investigated in as much detail. We have used a natural model of cytoskeletal dysfunction caused by deficiency of the Wiskott-Aldrich syndrome protein (WASp) to explore the contribution of the DC cytoskeleton to IS formation and to T-cell priming. In an antigen-specific system, T-DC contacts were found to be less stable when DCs alone lacked WASp, and associated with multiple defects of IS structure. As a consequence, DCs were unable to support normal IL-12 secretion, and events downstream of TCR signaling were abrogated, including increased calcium flux, microtubule organizing center (MTOC) polarization, phosphorylation of ZAP-70, andT-cell proliferation. Formation of an effective signaling interface is therefore dependent on active cytoskeletal rearrangements in DCs even when T cells are functionally competent. Deficiency of DC-mediated activities may contribute significantly to the varied immunodysregulation observed in patients with WAS, and also in those with limited myeloid reconstitution after allogeneic hematopoietic stem cell transplantation. (Blood. 2011;118(9):2492-2501)