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- Title
CCR7 acts as both a sensor and a sink for CCL19 to coordinate collective leukocyte migration.
- Authors
Alanko, Jonna; Uçar, Mehmet Can; Canigova, Nikola; Stopp, Julian; Schwarz, Jan; Merrin, Jack; Hannezo, Edouard; Sixt, Michael
- Abstract
Immune responses rely on the rapid and coordinated migration of leukocytes. Whereas it is well established that single-cell migration is often guided by gradients of chemokines and other chemoattractants, it remains poorly understood how these gradients are generated, maintained, and modulated. By combining experimental data with 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 a 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, dynamically shaping the spatiotemporal 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, and provide a guidance cue for other comigrating cells. Such a dual role of CCR7 as a GPCR that both senses and consumes its ligand can thus provide a novel mode of cellular self-organization. Editor's summary: Dendritic cells (DCs) migrate over long distances to shuttle antigen from peripheral tissues to lymph nodes. Immune cell trafficking is mediated by chemotactic gradients, but whether DCs can modulate these gradients is unknown. Using a combination of live cell imaging and mathematical modeling, Alanko et al. identify a dual role for the GPCR CCR7 in controlling DC migration. In addition to sensing CCL19 through CCR7, DCs were able to modulate local chemokine concentration via Lfc-mediated endocytosis of CCR7, "sinking" CCL19 from the environment. This self-shaping of chemokine gradients facilitated the accurate migration of DCs, and these gradients could also be sensed by T cells. Together these findings demonstrate that CCR7 can function as both a sensor and a sink for CCL19, facilitating collective leukocyte migration. – Hannah Isles
- Publication
Science Immunology, 2023, Vol 8, Issue 87, p1
- ISSN
2470-9468
- Publication type
Article
- DOI
10.1126/sciimmunol.adc9584