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Differential CCR7 Targeting in Dendritic Cells by Three Naturally Occurring CC-Chemokines

Lookup NU author(s): Professor Simi Ali



This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).


The CCR7 ligands CCL19 and CCL21 are increasingly recognized as functionally different (biased). Using mature human dendritic cells (DCs), we show that CCL19 is more potent than CCL21 in inducing 3D chemotaxis. Intriguingly, CCL21 induces prolonged and more efficient ERK1/2 activation compared with CCL19 and a C-terminal truncated (tailless) CCL21 in DCs. In contrast, tailless-CCL21 displays increased potency in DC chemotaxis compared with native CCL21. Using a CCL21-specific antibody, we show that CCL21, but not tailless-CCL21, accumulates at the cell surface. In addition, removal of sialic acid from the cell surface by neuraminidase treatment impairs ERK1/2 activation by CCL21, but not by CCL19 or tailless-CCL21. Using standard laboratory cell lines, we observe low potency of both CCL21 and tailless-CCL21 in G protein activation and beta-arrestin recruitment compared with CCL19, indicating that the tail itself does not improve receptor interaction. Chemokines interact with their receptors in a stepwise manner with ultimate docking of their N-terminus into the main binding pocket. Employing site-directed mutagenesis we identify residues in this pocket of selective CCL21 importance. We also identify a molecular switch in the top of TM7 important for keeping CCR7 in an inactive conformation (Tyr312), as introduction of the chemokine receptor-conserved Glu (or Ala) induces high constitutive activity. Summarized, we show that the interaction of the tail of CCL21 with polysialic acid is needed for strong ERK signaling, whereas it impairs CCL21-mediated chemotaxis and has no impact on receptor docking consistent with the current model of chemokine: receptor interaction. This indicates that future selective pharmacological targeting of CCL19 versus CCL21 should focus on a differential targeting of the main receptor pocket, while selective targeting of tailless-CCL21 versus CCL21 and CCL19 requires targeting of the glycosaminoglycan (GAG) interaction.

Publication metadata

Author(s): Hjortø GM, Larsen O, Steen A, Daugvilaite V, Berg C, Fares S, Hansen M, Ali S, Rosenkilde MM

Publication type: Article

Publication status: Published

Journal: Frontiers in Immunology

Year: 2016

Volume: 7

Online publication date: 09/12/2016

Acceptance date: 22/11/2016

Date deposited: 15/02/2017

ISSN (electronic): 1664-3224

Publisher: Frontiers Research Foundation


DOI: 10.3389/fimmu.2016.00568


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Funder referenceFunder name
A. P. Moller Foundation for the Advancement of Medical Science
Gangsted Foundation
Novo Nordisk Foundation
Aase and Einar Danielsen Foundation
Danish Council for Independent Research, Medical Sciences
Fonden for Neurologisk forskning
Horslev Foundation
Lundbeck Foundation
606979FP7-MC-ITN (POSAT)
FP7-MC-ITN (POSAT, 606979)