Chemoattractant-mediated recruitment of hematopoietic cells to sites of pathogen growth or tissue damage is critical to host defense and organ homeostasis. Chemotaxis is typically considered to rely on spatial sensing, with cells following concentration gradients as long as these are present. Utilizing a microfluidic approach, we found that stable gradients of intermediate chemokines (CCL19 and CXCL12) failed to promote persistent directional migration of dendritic cells or neutrophils. Instead, rising chemokine concentrations were needed, implying that temporal sensing mechanisms controlled prolonged responses to these ligands. This behavior was found to depend on G-coupled receptor kinase-mediated negative regulation of receptor signaling and contrasted with responses to an end agonist chemoattractant (C5a), for which a stable gradient led to persistent migration. These findings identify temporal sensing as a key requirement for long-range myeloid cell migration to intermediate chemokines and provide insights into the mechanisms controlling immune cell motility in complex tissue environments.

趋化因子介导的造血细胞募集到病原体生长或组织损伤的部位对于宿主防御和器官稳态至关重要。通常认为趋化性依赖于空间感测，只要浓度梯度存在，细胞就会遵循浓度梯度。利用微流体方法，我们发现中间趋化因子（CCL19和CXCL12）的稳定梯度不能促进树突状细胞或嗜中性粒细胞的持久定向迁移。相反，需要增加趋化因子浓度，这意味着时间感测机制控制了对这些配体的延长响应。发现这种行为依赖于G偶联受体激酶介导的受体信号传导负调节，并与对末端激动剂趋化剂（C5a）的反应形成对比，稳定的梯度导致持续的迁移。这些发现确定了时间感测是远程髓样细胞向中间趋化因子迁移的关键要求，并为复杂组织环境中控制免疫细胞运动的机制提供了见识。