Dendritic Cells Interpret Haptotactic Chemokine Gradients in a Manner Governed by Signal-to-Noise Ratio and Dependent on GRK6

Abstract

Navigation of cells along gradients of guidance cues is a determining step in many developmental and immunological processes. Gradients can either be soluble or immobilized to tissues as demonstrated for the haptotactic migration of dendritic cells (DCs) toward higher concentrations of immobilized chemokine CCL21. To elucidate how gradient characteristics govern cellular response patterns, we here introduce an in vitro system allowing to track migratory responses of DCs to precisely controlled immobilized gradients of CCL21. We find that haptotactic sensing depends on the absolute CCL21 concentration and local steepness of the gradient, consistent with a scenario where DC directionality is governed by the signal-to-noise ratio of CCL21 binding to the receptor CCR7. We find that the conditions for optimal DC guidance are perfectly provided by the CCL21 gradients we measure in vivo. Furthermore, we find that CCR7 signal termination by the G-protein-coupled receptor kinase 6 (GRK6) is crucial for haptotactic but dispensable for chemotactic CCL21 gradient sensing in vitro and confirm those observations in vivo. These findings suggest that stable, tissue-bound CCL21 gradients as sustainable "roads" ensure optimal guidance in vivo.

Migrating Myeloid Cells Sense Temporal Dynamics of Chemoattractant Concentrations

“…Moreover, all three mutant populations showed stronger persistence in rising gradients of CCL19, albeit at a lower absolute level than wild-type cells did in response to CXCL12. GRK6, in particular, appears to play complex roles, as indicated by the fact that it recently was found to be important for chemotaxis along surface-bound gradients while being dispensable for soluble ones (Schwarz et al, 2017). …”

“…With soluble ligands, the migration rate is presumably too slow to overcome the faster rate of desensitization and a rising input of chemokine is needed to sustain motility. Interestingly, even for bound chemokines, the same research group recently found that exponentially increasing chemokine concentrations are required for persistent chemotaxis towards CCL21 (Schwarz et al, 2017). One possible explanation for the requirement for exponential gradients would be that in exponential gradients the relative concentration difference across the cell diameter (difference between front and back concentration divided by absolute concentration) stays constant whereas it decreases in linear gradients as the absolute concentration increases.…”

Glycosaminoglycan Interactions with Chemokines Add Complexity to a Complex System

“…In this review we summarize the structural diversity of chemokine–GAG interactions, which suggests chemokine-specific regulation by GAGs. These diverse interactions not only regulate the formation and location of the chemokine gradient, but also its physical properties (e.g., composition, steepness and duration [ 14 , 25 , 26 , 27 , 28 , 29 ]). We also highlight emerging evidence for the involvement of chemokine–GAG interactions in other aspects of chemokine function, such as chemokine stability, negative and positive regulation of receptor activation, and remodeling the cellular glycocalyx, potentially to facilitate cell–cell interactions and transcytosis [ 30 , 31 , 32 , 33 , 34 , 35 , 36 ].…”

Different integrins mediate haptotaxis of T lymphocytes towards either lower or higher adhesion zones

“…Directed motion is a hallmark of the immune response. Leukocytes are sensitive to mechanical cues like blood flow (mechanotaxis) (5)(6)(7)(8), to soluble biochemical cues like bacterial fragments or chemokines (chemotaxis) (1,9), and to anchored signaling molecules like chemokines CCL21 or IL8 (haptotaxis) (10)(11)(12). However, if directed motion by adhesion molecules (adhesive haptotaxis) is well documented for cancer cells, fibroblasts, endothelial cells or neurons (13)(14)(15)(16)(17)(18)(19)(20)(21)(22), it has not been evidenced for leukocytes yet.…”