Nolz Jeffrey C, Gomez Timothy S, Zhu Peimin, Li Shuixing, Medeiros Ricardo B, Shimizu Yoji, Burkhardt Janis K, Freedman Bruce D, Billadeau Daniel D
Department of Immunology, Mayo Clinic College of Medicine, Rochester, Minnesota 55905, USA.
Curr Biol. 2006 Jan 10;16(1):24-34. doi: 10.1016/j.cub.2005.11.036.
The engagement of the T cell receptor results in actin cytoskeletal reorganization at the immune synapse (IS) and the triggering of biochemical signaling cascades leading to gene regulation and, ultimately, cellular activation. Recent studies have identified the WAVE family of proteins as critical mediators of Rac1-induced actin reorganization in other cell types. However, whether these proteins participate in actin reorganization at the IS or signaling pathways in T cells has not been investigated.
By using a combination of biochemical, genetic, and cell biology approaches, we provide evidence that WAVE2 is recruited to the IS, is biochemically modified, and is required for actin reorganization and beta-integrin-mediated adhesion after TCR crosslinking. Moreover, we show that WAVE2 regulates calcium entry at a point distal to PLCgamma1 activation and IP(3)-mediated store release.
These data reveal a role for WAVE2 in regulating multiple pathways leading to T cell activation. In particular, this work shows that WAVE2 is a key component of the actin regulatory machinery in T cells and that it also participates in linking intracellular calcium store depletion to calcium release-activated calcium (CRAC) channel activation.
T细胞受体的激活会导致免疫突触（IS）处肌动蛋白细胞骨架重排，并引发生化信号级联反应，进而导致基因调控，最终引起细胞活化。最近的研究已确定WAVE蛋白家族是其他细胞类型中Rac1诱导的肌动蛋白重排的关键介质。然而，这些蛋白是否参与T细胞免疫突触处的肌动蛋白重排或信号通路尚未得到研究。
通过结合生化、遗传和细胞生物学方法，我们提供证据表明，TCR交联后，WAVE2被招募到免疫突触，发生生化修饰，并且是肌动蛋白重排和β-整合素介导的黏附所必需的。此外，我们表明WAVE2在PLCγ1激活和IP(3)介导的钙库释放的远端调节钙内流。
这些数据揭示了WAVE2在调节导致T细胞活化的多种途径中的作用。特别是，这项工作表明WAVE2是T细胞中肌动蛋白调节机制的关键组成部分，并且它还参与将细胞内钙库耗竭与钙释放激活钙（CRAC）通道激活联系起来。
