CCR7-mediated LFA-1 functions in T cells are regulated by 2 independent ADAP/SKAP55 modules
CCR7-mediated LFA-1 functions in T cells are regulated by 2 independent ADAP/SKAP55 modules
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DOI：
10.1182/blood-2011-06-362269
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发表时间：
2012-01-19
期刊：
影响因子：
20.3
通讯作者：
Schraven, Burkhart
中科院分区：
文献类型：
--
作者：
Kliche, Stefanie;Worbs, Tim;Schraven, Burkhart
β 2-整联蛋白淋巴细胞功能相关抗原-1（LFA-1）在免疫系统中起着至关重要的作用。它调节T细胞和抗原呈递细胞之间的相互作用，并促进T细胞粘附于内皮，这是淋巴细胞外渗和归巢的重要过程。通过T细胞受体和趋化因子受体CCR 7介导的信号通过称为由内向外信号传导的过程激活LFA-1。由内而外信号传导的分子机制尚未完全理解。在这里，我们评估了ADAP/SKAP 55模块在CCR 7介导的信号传导中的作用。我们发现，模块的损失延迟归巢，并减少体内的结内T细胞运动。这可能是因为CCR 7介导的粘附缺陷影响LFA-1的亲和力和亲合力调节。对ADAP/SKAP 55模块如何调节CCR 7诱导的整合素活化的进一步分析显示，该模块的2个独立库在T细胞中表达。一个池与RAPL/Mst 1复合物相互作用，而另一个池与RIAM/Mst 1/Kindlin-3复合物连接。重要的是，RAPL/Mst 1和RIAM/Mst 1/Kindlin-3复合物都需要ADAP/SKAP 55在CCR 7刺激后与LFA-1结合。因此，2个独立的ADAP/SKAP 55模块是调节LFA-1响应于CCR 7的亲和力和亲合力的信号传导机制的重要组成部分。（血。2012;119（3）：777-785）
The beta 2-integrin lymphocyte function-associated antigen-1 (LFA-1) plays a crucial role within the immune system. It regulates the interaction between T cells and antigen-presenting cells and facilitates T-cell adhesion to the endothelium, a process that is important for lymphocyte extravasation and homing. Signals mediated via the T-cell receptor and the chemokine receptor CCR7 activate LFA-1 through processes known as inside-out signaling. The molecular mechanisms underlying inside-out signaling are not completely understood. Here, we have assessed the role of the ADAP/SKAP55 module for CCR7-mediated signaling. We show that loss of the module delays homing and reduces intranodal T-cell motility in vivo. This is probably because of a defect in CCR7-mediated adhesion that affects both affinity and avidity regulation of LFA-1. Further analysis of how the ADAP/SKAP55 module regulates CCR7-induced integrin activation revealed that 2 independent pools of the module are expressed in T cells. One pool interacts with a RAPL/Mst1 complex, whereas the other pool is linked to a RIAM/Mst1/Kindlin-3 complex. Importantly, both the RAPL/Mst1 and the RIAM/Mst1/Kindlin-3 complexes require ADAP/SKAP55 for binding to LFA-1 upon CCR7 stimulation. Hence, 2 independent ADAP/SKAP55 modules are essential components of the signaling machinery that regulates affinity and avidity of LFA-1 in response to CCR7. (Blood. 2012;119(3):777-785)