Dendritic Cells Interpret Haptotactic Chemokine Gradients in a Manner Governed by Signal-to-Noise Ratio and Dependent on GRK6
Dendritic Cells Interpret Haptotactic Chemokine Gradients in a Manner Governed by Signal-to-Noise Ratio and Dependent on GRK6
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DOI：
10.1016/j.cub.2017.04.004
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发表时间：
2017-05-08
期刊：
影响因子：
9.2
通讯作者：
Sixt, Michael
中科院分区：
文献类型：
--
作者：
Schwarz, Jan;Bierbaum, Veronika;Sixt, Michael
细胞沿着引导线索的梯度导航是许多发育和免疫过程的决定性步骤。梯度既可以溶解，也可以固定在组织中，如树突状细胞（dc）向高浓度的固定化趋化因子CCL21的触致迁移。为了阐明梯度特征如何控制细胞反应模式，我们在这里介绍了一个体外系统，该系统允许跟踪DCs对精确控制的CCL21固定梯度的迁移反应。我们发现，触觉传感取决于CCL21的绝对浓度和局部梯度的陡峭度，这与CCL21与受体CCR7结合的信噪比控制DC方向性的情况一致。我们发现体内测量的CCL21梯度完美地提供了最佳直流引导的条件。此外，我们发现g蛋白偶联受体激酶6 （GRK6）的CCR7信号终止对体外趋化CCL21梯度传感至关重要，但对体外趋化CCL21梯度传感却必不可少，并在体内证实了这些观察结果。这些发现表明，稳定的、组织结合的CCL21梯度作为可持续的“道路”确保了体内的最佳引导。
Navigation of cells along gradients of guidance cues is a determining step in many developmental and immunological processes. Gradients can either be soluble or immobilized to tissues as demonstrated for the haptotactic migration of dendritic cells (DCs) toward higher concentrations of immobilized chemokine CCL21. To elucidate how gradient characteristics govern cellular response patterns, we here introduce an in vitro system allowing to track migratory responses of DCs to precisely controlled immobilized gradients of CCL21. We find that haptotactic sensing depends on the absolute CCL21 concentration and local steepness of the gradient, consistent with a scenario where DC directionality is governed by the signal-to-noise ratio of CCL21 binding to the receptor CCR7. We find that the conditions for optimal DC guidance are perfectly provided by the CCL21 gradients we measure in vivo. Furthermore, we find that CCR7 signal termination by the G-protein-coupled receptor kinase 6 (GRK6) is crucial for haptotactic but dispensable for chemotactic CCL21 gradient sensing in vitro and confirm those observations in vivo. These findings suggest that stable, tissue-bound CCL21 gradients as sustainable "roads'' ensure optimal guidance in vivo.