Identification of critical residues at the C-terminal tip of ACKR4 regulating chemokine internalization and βarrestin involvement.

Background: Atypical chemokine receptors (ACKRs) play an important role in regulating the availability of chemokines and are responsible for the formation of chemokine gradients required for the directed migration of immune cells in health and disease. ACKR4 shapes gradients of the chemokines CCL19 and CCL21, which are essential for guiding leukocyte homing to lymphoid organs where they initiate an adaptive immune response against invading pathogens. How ACKRs internalize and scavenge chemokines on the molecular level remains poorly understood.

GPR182 is a broadly scavenging atypical chemokine receptor influencing T-independent immunity.

Immune responses highly depend on the effective trafficking of immune cells into and within secondary lymphoid organs (SLOs). Atypical chemokine receptors (ACKRs) scavenge chemokines to eliminate them from the extracellular space, thereby generating gradients that guide leukocytes. In contrast to canonical chemokine receptors, ACKRs do not induce classical intracellular signaling that results in cell migration.

Heparin Specifically Interacts with Basic BBXB Motifs of the Chemokine CCL21 to Define CCR7 Signaling.

Chemokines are critically involved in controlling directed leukocyte migration. Spatiotemporal secretion together with local retention processes establish and maintain local chemokine gradients that guide directional cell migration. Extracellular matrix proteins, particularly glycosaminoglycans (GAGs), locally retain chemokines through electrochemical interactions.

Distinct Fates of Chemokine and Surrogate Molecule Gradients: Consequences for CCR7-Guided Dendritic Cell Migration.

Chemokine-guided leukocyte migration is a hallmark of the immune system to cope with invading pathogens. Intruder confronted dendritic cells (DCs) induce the expression of the chemokine receptor CCR7, which enables them to sense and migrate along chemokine gradients to home to draining lymph nodes, where they launch an adaptive immune response. Chemokine-mediated DC migration is recapitulated and intensively studied in 3D matrix migration chambers.

Shifting CCR7 towards Its Monomeric Form Augments CCL19 Binding and Uptake.

The chemokine receptor CCR7, together with its ligands, is responsible for the migration and positioning of adaptive immune cells, and hence critical for launching adaptive immune responses. CCR7 is also induced on certain cancer cells and contributes to metastasis formation. Thus, CCR7 expression and signalling must be tightly regulated for proper function.

A Versatile Toolkit for Semi-Automated Production of Fluorescent Chemokines to Study CCR7 Expression and Functions.

Chemokines guide leukocyte migration in different contexts, including homeostasis, immune surveillance and immunity. The chemokines CCL19 and CCL21 control lymphocyte and dendritic cell migration and homing to lymphoid organs. Thereby they orchestrate adaptive immunity in a chemokine receptor CCR7-dependent manner.