CCR7 acts as both a sensor and a sink for CCL19 to coordinate collective leukocyte migration

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.

From the Skin to Distant Sites: T Cells in Psoriatic Disease

“…Subsequent studies indicated the interaction between the chemokine, CCL19, and its ligand CCR7, which is typical of T cell activation in lymphoid structures as a key event for the recruitment of these cells also in psoriatic skin [72]. In the dermis of psoriatic plaques, the presence of a lymphoid aggregates has been reported by Mitsui and colleagues, evidencing also the expression of CCL19 and CCR7 [73].…”

CAR-T lymphocyte-based cell therapies; mechanistic substantiation, applications and biosafety enhancement with suicide genes: new opportunities to melt side effects

“…Focusing on the cycle of the anti-tumor immune response ( Figure 3 ), it begins with the release and capture of neoantigens, generated during oncogenesis, by antigen-presenting cells (APCs), such as dendritic cells (DCs). These cells process the antigens and undergo a maturation process, which involves an increase in the expression of various molecules, such as the chemokine receptor CCR7 ( 24 – 26 )and the migration of DCs to the lymph nodes where they can interact with T cells ( 24 ), driving complex collective migration patterns, allowing DCs to create or enhance chemotactic gradients ( 24 ). For an anti-tumor T response to be generated, this process needs to be accompanied by signals that prevent peripheral tolerance to tumor antigens, such as high expression of major histocompatibility complex (MHC) molecules and co-stimulatory molecules (such as CD80, IL1, IFN-α) ( 27 ).…”

Dendritic Cell-Based Immunotherapy: The Importance of Dendritic Cell Migration

“…Through this internalization process, DCs generate a self-generated chemokine gradient. However, when chemokine gradients are low, DCs are difficult to perceive, whereas high gradients lead to receptor saturation, hindering cells from sensing spatial differences [ 71 – 73 ]. Stable gradients of CCL19 are crucial for stabilizing directionality because disruption of these gradients leads to impaired cytoskeletal polarization and persistent chemotaxis.…”