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 ζ-chain phosphorylation, and more downstream signaling events. Acute inhibition of Csk revealed that CD45 suppressed ζ-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.

中文翻译：

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CD45 在 T 细胞中充当信号看门人。

T 细胞需要蛋白酪氨酸磷酸酶 CD45 来检测和响应抗原，因为它会激活 Src 家族激酶 Lck，后者可磷酸化 T 细胞抗原受体 (TCR) 复合物。CD45 通过对抗负调节激酶 Csk 激活 Lck。矛盾的是，CD45 还与通过去磷酸化 Lck 作用的 TCR 复合物中相同的信号基序来抑制 TCR 信号传导有关。我们试图通过结合计算分析的 Csk/CD45 调节轴的化学和遗传扰动来协调这些观察结果。具体来说，我们滴定了 Csk 和 CD45 的活性，并评估了它们对 Lck 激活、TCR 相关 ζ 链磷酸化和更多下游信号事件的影响。对 Csk 的急性抑制表明，CD45 抑制了 ζ 链磷酸化，并且是可调节的活性 Lck 池所必需的，从而将 CD45 调节抗原识别的激活和抑制作用相互关联。CD45 抑制与抗原无关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引发的信号事件。总之，我们的研究结果表明，CD45 充当信号“看门人”，在过滤弱或虚假信号事件的同时实现分级信号输出。