Sinking the way: a dual role for CCR7 in collective leukocyte migration

Abstract

Immune responses crucially rely on the rapid and coordinated locomotion of leukocytes. While it is well established that single-cell migration is often guided by gradients of chemokines and other chemoattractants, it remains poorly understood how such gradients are generated, maintained and modulated. Combining experiment and theory on leukocyte chemotaxis guided by the G protein-coupled receptor (GPCR) CCR7, we demonstrate that in addition to its role as the sensory receptor that steers migration, CCR7 also acts as a generator and modulator of chemotactic gradients. Upon exposure to the CCR7 ligand CCL19, dendritic cells (DCs) effectively internalize the receptor and ligand as part of the canonical GPCR-desensitization response. We show that CCR7 internalization also acts as an effective sink for the chemoattractant, thereby dynamically shaping the spatio-temporal distribution of the chemokine. This mechanism drives complex collective migration patterns, enabling DCs to create or sharpen chemotactic gradients. We further show that these self-generated gradients can sustain the long-range guidance of DCs, adapt collective migration patterns to the size and geometry of the environment, as well as provide a guidance cue for other co-migrating cells. Such dual role of CCR7 as a GPCR that both senses and consumes its ligand can thus provide a novel mode of cellular self-organization.

A self-generated Toddler gradient guides mesodermal cell migration

“…We provide direct experimental in vivo evidence that a GPCR, namely, the Aplnr, indeed executes both scavenger and sensor roles, acting as the sole molecular player in generating and sensing the directional cue that guides mesodermal cells to the animal pole. A conceptually similar finding, namely, that signaling GPCRs modulate extracellular guidance cues, has been reported for immune cell migration while this study was under review (37). The chemokine receptor CCR7 was shown to both sense and self-generate functional CCL19 chemokine gradients in vitro, thereby collectively organizing the comigration of several immune cell types.…”