Three-Dimensional Gradients of Cytokine Signaling between T Cells.
Three-Dimensional Gradients of Cytokine Signaling between T Cells.
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DOI：
10.1371/journal.pcbi.1004206
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发表时间：
2015-04
影响因子：
4.3
通讯作者：
Höfer T
中科院分区：
文献类型：
--
作者：
Thurley K;Gerecht D;Friedmann E;Höfer T
免疫反应由可扩散介质细胞因子调节，其作用浓度为亚纳摩尔浓度。细胞因子通讯的空间范围是一个至关重要但仍知之甚少的功能特性。人们已经提出了在免疫细胞（免疫突触）之间的狭窄连接处抑制细胞因子作用和遍及整个淋巴结的全局信号传导，但它们可能发生的条件尚不清楚。在这里，我们分析了两个连续尺度上细胞因子信号传导动力学的空间三维反应扩散模型：免疫突触和密集的多细胞环境。对于实际参数值，我们观察局部空间梯度，分泌细胞周围的细胞因子浓度仅在几个细胞直径上急剧衰减。我们重点关注已充分表征的 T 细胞细胞因子白细胞介素 2，展示了细胞因子分泌和竞争性摄取如何决定该信号传导范围。吸收是由免疫突触的几何形状局部决定的。然而，即使对于有利于突触内细胞因子消耗的狭窄突触，预计进入突触外空间的逃逸通量也将是大量的（≥分泌的20%）。因此，旁分泌信号通常会延伸到突触之外，但可以通过靶细胞或强大的竞争者（例如调节性 T 细胞）的摄取而限制在细胞微环境中。相比之下，长程细胞因子信号传导需要高密度的细胞因子产生者或弱消耗（例如，通过稀疏分布的靶细胞）。因此，在生理环境中，细胞之间的细胞因子梯度，而不是体相浓度，对于细胞间的通讯至关重要，这强调了细胞因子信号传导空间解析数据的需要。适应性免疫系统通过激活特异性识别特定病原体的免疫细胞克隆来对抗病原体。免疫细胞与呈现“消化”病原体分子的细胞的紧密接触，即所谓的免疫突触，对于确保特异性至关重要。免疫反应由小的可扩散蛋白质（细胞因子）调节的发现令人惊讶，因为细胞因子扩散到“旁观者”细胞可能会损害特异性。因此，有人认为细胞因子被捕获在免疫突触中，而其他作者发现细胞因子通过整个淋巴结更大规模地发挥作用。尚未实现具有精细空间分辨率的细胞因子浓度测量。在这里，我们通过数学分析和三维数值模拟研究细胞因子的时空动态，并确定控制信号范围的关键参数。我们预测，即使是紧密的免疫突触也会泄漏大部分分泌的细胞因子。然而，快速的细胞摄取将使细胞因子信号短程，因此可以限制旁观细胞的偶然激活。长程信号仅在多个分泌细胞或/和稀疏目标细胞缓慢消耗的情况下发生。因此，我们的研究确定了现实多细胞几何结构中细胞因子通讯空间范围的关键决定因素。
Immune responses are regulated by diffusible mediators, the cytokines, which act at sub-nanomolar concentrations. The spatial range of cytokine communication is a crucial, yet poorly understood, functional property. Both containment of cytokine action in narrow junctions between immune cells (immunological synapses) and global signaling throughout entire lymph nodes have been proposed, but the conditions under which they might occur are not clear. Here we analyze spatially three-dimensional reaction-diffusion models for the dynamics of cytokine signaling at two successive scales: in immunological synapses and in dense multicellular environments. For realistic parameter values, we observe local spatial gradients, with the cytokine concentration around secreting cells decaying sharply across only a few cell diameters. Focusing on the well-characterized T-cell cytokine interleukin-2, we show how cytokine secretion and competitive uptake determine this signaling range. Uptake is shaped locally by the geometry of the immunological synapse. However, even for narrow synapses, which favor intrasynaptic cytokine consumption, escape fluxes into the extrasynaptic space are expected to be substantial (≥20% of secretion). Hence paracrine signaling will generally extend beyond the synapse but can be limited to cellular microenvironments through uptake by target cells or strong competitors, such as regulatory T cells. By contrast, long-range cytokine signaling requires a high density of cytokine producers or weak consumption (e.g., by sparsely distributed target cells). Thus in a physiological setting, cytokine gradients between cells, and not bulk-phase concentrations, are crucial for cell-to-cell communication, emphasizing the need for spatially resolved data on cytokine signaling. The adaptive immune system fights pathogens through the activation of immune cell clones that specifically recognize a particular pathogen. Tight contacts, so-called immunological synapses, of immune cells with cells that present ‘digested’ pathogen molecules are pivotal for ensuring specificity. The discovery that immune responses are regulated by small diffusible proteins – the cytokines – has been surprising because cytokine diffusion to ‘bystander’ cells might compromise specificity. It has therefore been argued that cytokines are trapped in immunological synapses, whereas other authors have found that cytokines act on a larger scale through entire lymph nodes. Measurements of cytokine concentrations with fine spatial resolution have not been achieved. Here, we study the spatio-temporal dynamics of cytokines through mathematical analysis and three-dimensional numerical simulation and identify key parameters that control signaling range. We predict that even tight immunological synapses leak a substantial portion of the secreted cytokines. Nevertheless, rapid cellular uptake will render cytokine signals short-range and thus incidental activation of bystander cells can be limited. Long-range signals will only occur with multiple secreting cells or/and slow consumption by sparse target cells. Thus our study identifies key determinants of the spatial range of cytokine communication in realistic multicellular geometries.
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影响因子：
16
作者：
Cohen-Saidon, Cellina;Cohen, Ariel A.;Alon, Uri
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Alon, Uri
影响因子：
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Shvartsman, Stanislav Y.
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通讯作者：
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