Ionic CD3-Lck interaction regulates the initiation of T-cell receptor signaling
Ionic CD3-Lck interaction regulates the initiation of T-cell receptor signaling
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离子 CD3-Lck 相互作用调节 T 细胞受体信号传导的启动
DOI：
10.1073/pnas.1701990114
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发表时间：
2017-07-18
影响因子：
11.1
通讯作者：
Xu, Chenqi
中科院分区：
文献类型：
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作者：
Li, Lunyi;Guo, Xingdong;Xu, Chenqi
抗原触发的T细胞受体(TCR)磷酸化是T细胞诱导对侵袭性病原体和肿瘤细胞产生适应性免疫的第一个信号事件。尽管具有重要的生理意义，但TCR磷酸化的潜在机制仍不清楚。在这里，我们报告了一个调控TCR磷酸化启动的关键机制。主要的TCR激酶Lck对TCR的四种CD3信号蛋白具有很高的选择性。CD3 epsilon是唯一能与Lck有效结合的CD3链，主要通过CD3 epsilon富含碱性残基序列(BRS)与Lck独特结构域中的酸性残基之间的离子相互作用实现。我们应用TCR重组系统来明确研究TCR磷酸化的启动。CD3epsilon-Lck离子相互作用控制整个TCR在抗原刺激下的磷酸化水平。CD3 epsilon BRs被隔离在膜上，抗原刺激可以解锁这个基序。因此，CD3 epsilon BRs的动态开放及其随后对Lck的募集可能是启动TCR磷酸化的重要开关。
Antigen-triggered T-cell receptor (TCR) phosphorylation is the first signaling event in T cells to elicit adaptive immunity against invading pathogens and tumor cells. Despite its physiological importance, the underlying mechanism of TCR phosphorylation remains elusive. Here, we report a key mechanism regulating the initiation of TCR phosphorylation. The major TCR kinase Lck shows high selectivity on the four CD3 signaling proteins of TCR. CD3 epsilon is the only CD3 chain that can efficiently interact with Lck, mainly through the ionic interactions between CD3 epsilon basic residue-rich sequence (BRS) and acidic residues in the Unique domain of Lck. We applied a TCR reconstitution system to explicitly study the initiation of TCR phosphorylation. The ionic CD3 epsilon-Lck interaction controls the phosphorylation level of the whole TCR upon antigen stimulation. CD3 epsilon BRS is sequestered in the membrane, and antigen stimulation can unlock this motif. Dynamic opening of CD3 epsilon BRS and its subsequent recruitment of Lck thus can serve as an important switch of the initiation of TCR phosphorylation.