Inflammation-Induced CCR7 Oligomers Form Scaffolds to Integrate Distinct Signaling Pathways for Efficient Cell Migration

Host defense depends on orchestrated cell migration guided by chemokines that elicit selective but biased signaling pathways to control chemotaxis. Here, we showed that different inflammatory stimuli provoked oligomerization of the chemokine receptor CCR7, enabling human dendritic cells and T cell subpopulations to process guidance cues not only through classical G protein-dependent signaling but also by integrating an oligomer-dependent Src kinase signaling pathway. Efficient CCR7-driven migration depends on a hydrophobic oligomerization interface near the conserved NPXXY motif of G protein-coupled receptors as shown by mutagenesis screen and a CCR7-SNP demonstrating super-oligomer characteristics leading to enhanced Src activity and superior chemotaxis. Furthermore, Src phosphorylates oligomeric CCR7, thereby creating a docking site for SH2-domain-bearing signaling molecules. Finally, we identified CCL21-biased signaling that involved the phosphatase SHP2 to control efficient cell migration. Collectively, our data showed that CCR7 oligomers serve as molecular hubs regulating distinct signaling pathways. [Display omitted] •Inflammatory signals and PGE2 induce CCR7 oligomerization to modulate DC migration•CCR7 oligomers serve as hubs to integrate distinct signaling pathways•Src phosphorylates oligomeric CCR7 to create a docking site for signaling molecules•Signaling bias involving SHP2 controls CCL21-driven cell migration Legler and colleagues show that inflammatory signals enable efficient DC and T cell migration by inducing CCR7 oligomerization, whereby the oligomer acts as hub to integrate G protein-dependent and Src kinase-dependent signaling. Src phosphorylates CCR7 to establish a docking site for SH2-domain molecules, including SHP2 that contributes to biased signaling to control CCL21-driven migration.