Dendritic cells interpret haptotactic chemokine gradients in a manner governed by signal to noise ratio and dependent on GRK6 Journal Article


Author(s): Schwarz, Jan; Bierbaum, Veronika; Vaahtomeri, Kari; Hauschild, Robert; Brown, Markus; de Vries, Ingrid; Leithner, Alexander; Reversat, Anne; Merrin, Jack; Tarrant, Teresa; Bollenbach, Tobias; Sixt, Michael
Article Title: Dendritic cells interpret haptotactic chemokine gradients in a manner governed by signal to noise ratio and dependent on GRK6
Affiliation IST Austria
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.
Keywords: Chemotaxis; leukocyte; gradient; cell migration; Chemokine; Polarity; dendritic cell; Haptotaxis; guidance; directed migration
Journal Title: Current Biology
Volume: 27
Issue 9
ISSN: 0960-9822
Publisher: Cell Press  
Date Published: 2017-05-09
Start Page: 1314
End Page: 1325
Sponsor: Boehringer Ingelheim Fonds, the European Research Council (ERC StG 281556), START Award from the Austrian Science Foundation (FWF Y564-B12)
DOI: 10.1016/j.cub.2017.04.004
Notes: We thank the Scientific Service Units of IST Austria for excellent support.
Open access: no