T cells selectively filter oscillatory signals on the minutes timescale.
T cells selectively filter oscillatory signals on the minutes timescale.
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DOI：
10.1073/pnas.2019285118
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发表时间：
2021-03-02
影响因子：
11.1
通讯作者：
Lim WA
中科院分区：
文献类型：
--
作者：
O'Donoghue GP;Bugaj LJ;Anderson W;Daniels KG;Rawlings DJ;Lim WA
体内的免疫细胞以复杂的时间模式遇到刺激，但我们对刺激的时机如何决定免疫反应的理解是不完整的。我们设计了从健康人类供体中获得的T细胞，使其在实验室环境中对光作为刺激做出反应。我们发现，T细胞可以仅根据信号频率过滤出特定信号，方法是用基于光的时间刺激模式刺激工程化T细胞，这些模式旨在模拟人体中天然T细胞可能经历的动态模式。这种过滤机制可能有助于免疫细胞如何在体内区分外来/改变的细胞与自身细胞，因为外来/改变的细胞和自身细胞表现出与体内T细胞高度不同的相互作用动力学。T细胞通过与周围细胞的受体-配体结合相互作用经历复杂的刺激时间模式。从这些时间模式中，T细胞能够在建立自身耐受性的同时挑选出抗原信号。虽然已经检查了抗原结合的持续时间等特征，但我们对T细胞如何解释具有不同频率或时间刺激模式的信号的理解相对未被探索。我们通过构建光遗传学控制的嵌合抗原受体（optoCAR）来改造T细胞以响应作为刺激的光。我们发现，T细胞通过用可调光脉冲序列刺激optoCAR T细胞来响应激活信号的分钟级振荡。从1到150分钟的系统扫描信号振荡周期显示，T细胞活化标志物CD 69的表达在大约25分钟的周期（对应于5到15分钟的脉冲宽度）达到局部最小值。抑制剂和基因敲除的组合表明，这种频率过滤机制位于T细胞应答网络的Erk信号传导分支的下游，并且可能涉及减少Erk活性的负反馈回路。CD 69过滤的时间尺度对应于通过小鼠体内活体成像观察到的T细胞与自我肽呈递APC相遇的持续时间，表明时间过滤在体内的潜在功能作用。这项研究表明，T细胞信号传导机制被调谐到时间上过滤和解释时变输入信号的歧视性方式。
Immune cells in the body encounter stimuli in complex temporal patterns, but our understanding of how the timing of stimulation determines immune responses is incomplete. We engineered T cells obtained from healthy human donors to respond to light as a stimulus in a laboratory setting. We discovered that T cells can filter out specific signals based only on signal frequency by stimulating engineered T cells with light-based temporal stimulation patterns designed to mimic the dynamic patterns a natural T cell might experience in the human body. This filtering mechanism could contribute to how immune cells distinguish between foreign/altered cells versus self-cells in vivo, since foreign/altered and self-cells exhibit highly distinct interaction dynamics with T cells within the body. T cells experience complex temporal patterns of stimulus via receptor–ligand-binding interactions with surrounding cells. From these temporal patterns, T cells are able to pick out antigenic signals while establishing self-tolerance. Although features such as duration of antigen binding have been examined, our understanding of how T cells interpret signals with different frequencies or temporal stimulation patterns is relatively unexplored. We engineered T cells to respond to light as a stimulus by building an optogenetically controlled chimeric antigen receptor (optoCAR). We discovered that T cells respond to minute-scale oscillations of activation signal by stimulating optoCAR T cells with tunable pulse trains of light. Systematically scanning signal oscillation period from 1 to 150 min revealed that expression of CD69, a T cell activation marker, reached a local minimum at a period of ∼25 min (corresponding to 5 to 15 min pulse widths). A combination of inhibitors and genetic knockouts suggest that this frequency filtering mechanism lies downstream of the Erk signaling branch of the T cell response network and may involve a negative feedback loop that diminishes Erk activity. The timescale of CD69 filtering corresponds with the duration of T cell encounters with self-peptide–presenting APCs observed via intravital imaging in mice, indicating a potential functional role for temporal filtering in vivo. This study illustrates that the T cell signaling machinery is tuned to temporally filter and interpret time-variant input signals in discriminatory ways.
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