A sharp T-cell antigen receptor signaling threshold for T-cell proliferation
A sharp T-cell antigen receptor signaling threshold for T-cell proliferation
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DOI：
10.1073/pnas.1413726111
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发表时间：
2014-09-02
影响因子：
11.1
通讯作者：
Weiss, Arthur
中科院分区：
文献类型：
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作者：
Au-Yeung, Byron B.;Zikherman, Julie;Weiss, Arthur
T细胞抗原受体（TCR）信号传导对于T细胞的活化、增殖和效应子功能是必需的。TCR信号传导的强度和持续时间的调节可以调节这些事件。然而，目前尚不清楚单个T细胞如何随着时间的推移整合这些信号，以做出关键的细胞命运决定。我们先前已经开发了关键T细胞激酶ζ链相关蛋白激酶70 kDa（Zap 70）的工程突变等位基因，其被小分子抑制剂催化抑制，从而特异性和有效地阻断TCR信号传导。我们还表征了荧光报告基因Nur 77-eGFP转基因小鼠系，其中T细胞独特地响应于TCR刺激而上调GFP。这些技术的组合揭示了用于体外和体内细胞分裂的尖锐TCR信号传导阈值。此外，我们证明，这个阈值是独立的TCR刺激和白细胞介素2的幅度。同样，我们确定了TCR信号传导的时间阈值，这是承诺增殖所需的，之后T细胞能够以Zap 70激酶非依赖性方式增殖。总之，我们的研究揭示了T细胞增殖所需的TCR信号传导的幅度和持续时间的明显阈值。这些结果对于理解T细胞对感染的反应和优化免疫调节药物递送策略具有重要意义。
T-cell antigen receptor (TCR) signaling is essential for activation, proliferation, and effector function of T cells. Modulation of both intensity and duration of TCR signaling can regulate these events. However, it remains unclear how individual T cells integrate such signals over time to make critical cell-fate decisions. We have previously developed an engineered mutant allele of the critical T-cell kinase zeta-chain-associated protein kinase 70 kDa (Zap70) that is catalytically inhibited by a small molecule inhibitor, thereby blocking TCR signaling specifically and efficiently. We have also characterized a fluorescent reporter Nur77-eGFP transgenic mouse line in which T cells up-regulate GFP uniquely in response to TCR stimulation. The combination of these technologies unmasked a sharp TCR signaling threshold for commitment to cell division both in vitro and in vivo. Further, we demonstrate that this threshold is independent of both the magnitude of the TCR stimulus and Interleukin 2. Similarly, we identify a temporal threshold of TCR signaling that is required for commitment to proliferation, after which T cells are able to proliferate in a Zap70 kinase-independent manner. Taken together, our studies reveal a sharp threshold for the magnitude and duration of TCR signaling required for commitment of T cells to proliferation. These results have important implications for understanding T-cell responses to infection and optimizing strategies for immunomodulatory drug delivery.