The large ectodomains of CD45 and CD148 regulate their segregation from and inhibition of ligated T-cell receptor
The large ectodomains of CD45 and CD148 regulate their segregation from and inhibition of ligated T-cell receptor
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DOI：
10.1182/blood-2012-07-442251
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发表时间：
2013-05-23
期刊：
影响因子：
20.3
通讯作者：
van der Merwe, P. Anton
中科院分区：
文献类型：
--
作者：
Cordoba, Shaun-Paul;Choudhuri, Kaushik;van der Merwe, P. Anton
T 细胞受体 (TCR) 触发导致细胞内酪氨酸磷酸化事件级联，最终导致 T 细胞激活。它取决于参与的 TCR 附近膜相关酪氨酸激酶和磷酸酶的相对活性的变化。 CD45 和 CD148 是具有大胞外域的跨膜酪氨酸磷酸酶，对 TCR 触发具有激活和抑制作用。本研究探讨了 CD45 和 CD148 的胞外域是否以及如何调节其对 TCR 信号传导的抑制作用。这些带有截短胞外域的磷酸酶在 T 细胞中的表达抑制了 TCR 触发。相反，当这些磷酸酶以大的胞外域表达时，它们没有抑制作用。影像学研究表明，胞外域的截短增强了这些磷酸酶与免疫突触处连接的 TCR 的共定位。我们的结果表明，CD45 和 CD148 的大胞外域通过使它们能够被动地、基于大小的与连接的 TCR 分离来调节它们的抑制作用，支持 TCR 触发的动力学分离模型。
T-cell receptor (TCR) triggering results in a cascade of intracellular tyrosine phosphorylation events that ultimately leads to T-cell activation. It is dependent on changes in the relative activities of membrane-associated tyrosine kinases and phosphatases near the engaged TCR. CD45 and CD148 are transmembrane tyrosine phosphatases with large ectodomains that have activatory and inhibitory effects on TCR triggering. This study investigates whether and how the ectodomains of CD45 and CD148 modulate their inhibitory effect on TCR signaling. Expression in T cells of forms of these phosphatases with truncated ectodomains inhibited TCR triggering. In contrast, when these phosphatases were expressed with large ectodomains, they had no inhibitory effect. Imaging studies revealed that truncation of the ectodomains enhanced colocalization of these phosphatases with ligated TCR at the immunological synapse. Our results suggest that the large ectodomains of CD45 and CD148 modulate their inhibitory effect by enabling their passive, size-based segregation from ligated TCR, supporting the kinetic-segregation model of TCR triggering.