CD45 functions as a signaling gatekeeper in T cells
CD45 functions as a signaling gatekeeper in T cells
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DOI：
10.1126/scisignal.aaw8151
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发表时间：
2019-10-22
影响因子：
7.3
通讯作者：
Weiss, Arthur
中科院分区：
文献类型：
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作者：
Courtney, Adam H.;Shvets, Alexey A.;Weiss, Arthur
T细胞需要蛋白酪氨酸磷酸酶CD45来检测和响应抗原，因为它激活了Src家族激酶Lck，使T细胞抗原受体(TCR)复合体磷酸化。CD45通过对抗负调控激酶CSK来激活Lck。矛盾的是，CD45还通过使LCK作用的TCR复合体中的相同信号基序去磷酸化来抑制TCR信号。我们试图利用CSK/CD45调节轴的化学和遗传扰动结合计算分析来协调这些观察结果。具体地说，我们滴定了CSK和CD45的活性，并评估了它们对LCK激活、TCR相关的-链磷酸化以及更多下游信号事件的影响。对CSK的急性抑制表明，CD45抑制了Zeta链的磷酸化，是可调节的活性Lck池所必需的，从而将调节抗原识别的CD45的激活和抑制作用联系起来。CD45抑制不依赖于抗原或由低亲和力抗原诱导的信号事件，但不抑制由高亲和力抗原启动的信号事件。综上所述，我们的研究结果显示，CD45充当信令“看门人”，在过滤弱或虚假信令事件的同时，实现分级信令输出。
T cells require the protein tyrosine phosphatase CD45 to detect and respond to antigen because it activates the Src family kinase Lck, which phosphorylates the T cell antigen receptor (TCR) complex. CD45 activates Lck by opposing the negative regulatory kinase Csk. Paradoxically, CD45 has also been implicated in suppressing TCR signaling by dephosphorylating the same signaling motifs within the TCR complex upon which Lck acts. We sought to reconcile these observations using chemical and genetic perturbations of the Csk/CD45 regulatory axis incorporated with computational analyses. Specifically, we titrated the activities of Csk and CD45 and assessed their influence on Lck activation, TCR-associated.-chain phosphorylation, and more downstream signaling events. Acute inhibition of Csk revealed that CD45 suppressed zeta-chain phosphorylation and was necessary for a regulatable pool of active Lck, thereby interconnecting the activating and suppressive roles of CD45 that tune antigen discrimination. CD45 suppressed signaling events that were antigen independent or induced by low-affinity antigen but not those initiated by high-affinity antigen. Together, our findings reveal that CD45 acts as a signaling "gatekeeper," enabling graded signaling outputs while filtering weak or spurious signaling events.