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CCL19 with CCL21-tail displays enhanced glycosaminoglycan binding with retained chemotactic potency in dendritic cells

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CCL19 with CCL21-tail displays enhanced glycosaminoglycan binding with retained chemotactic potency in dendritic cells

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JØRGENSEN, Astrid S., Pontian E. ADOGAMHE, Julia M. LAUFER, Daniel F. LEGLER, Christopher T. VELDKAMP, Mette M. ROSENKILDE, Gertrud M. HJORTØ, 2018. CCL19 with CCL21-tail displays enhanced glycosaminoglycan binding with retained chemotactic potency in dendritic cells. In: Journal of leukocyte biology. 104(2), pp. 401-411. ISSN 0741-5400. eISSN 1938-3673. Available under: doi: 10.1002/JLB.2VMA0118-008R

@article{Jrgensen2018-08CCL19-42812, title={CCL19 with CCL21-tail displays enhanced glycosaminoglycan binding with retained chemotactic potency in dendritic cells}, year={2018}, doi={10.1002/JLB.2VMA0118-008R}, number={2}, volume={104}, issn={0741-5400}, journal={Journal of leukocyte biology}, pages={401--411}, author={Jørgensen, Astrid S. and Adogamhe, Pontian E. and Laufer, Julia M. and Legler, Daniel F. and Veldkamp, Christopher T. and Rosenkilde, Mette M. and Hjortø, Gertrud M.} }

Hjortø, Gertrud M. eng Laufer, Julia M. Hjortø, Gertrud M. terms-of-use CCL19 is more potent than CCL21 in inducing chemotaxis of human dendritic cells (DC). This difference is attributed to 1) a stronger interaction of the basic C-terminal tail of CCL21 with acidic glycosaminoglycans (GAGs) in the environment and 2) an autoinhibitory function of this C-terminal tail. Moreover, different receptor docking modes and tissue expression patterns of CCL19 and CCL21 contribute to fine-tuned control of CCR7 signaling. Here, we investigate the effect of the tail of CCL21 on chemokine binding to GAGs and on CCR7 activation. We show that transfer of CCL21-tail to CCL19 (CCL19<sup>CCL21-tail</sup> ) markedly increases binding of CCL19 to human dendritic cell surfaces, without impairing CCL19-induced intracellular calcium release or DC chemotaxis, although it causes reduced CCR7 internalization. The more potent chemotaxis induced by CCL19 and CCL19<sup>CCL21-tail</sup> compared to CCL21 is not transferred to CCL21 by replacing its N-terminus with that of CCL19 (CCL21<sup>CCL19-N-term</sup> ). Measurements of cAMP production in CHO cells uncover that CCL21-tail transfer (CCL19<sup>CCL21-tail</sup> ) negatively affects CCL19 potency, whereas removal of CCL21-tail (<sup>CCL21tailless</sup> ) increases signaling compared to full-length CCL21, indicating that the tail negatively affects signaling via cAMP. Similar to chemokine-driven calcium mobilization and chemotaxis, the potency of CCL21 in cAMP is not improved by transfer of the CCL19 N-terminus to CCL21 (CCL21<sup>CCL19-N-term</sup> ). Together these results indicate that ligands containing CCL21 core and C-terminal tail (CCL21 and CCL21<sup>CCL19-N-term</sup> ) are most restricted in their cAMP signaling; a phenotype attributed to a stronger GAG binding of CCL21 and defined structural differences between CCL19 and CCL21. Rosenkilde, Mette M. Adogamhe, Pontian E. Adogamhe, Pontian E. Jørgensen, Astrid S. CCL19 with CCL21-tail displays enhanced glycosaminoglycan binding with retained chemotactic potency in dendritic cells Laufer, Julia M. Legler, Daniel F. Veldkamp, Christopher T. 2018-08 Legler, Daniel F. 2018-07-07T14:08:26Z 2018-07-07T14:08:26Z Veldkamp, Christopher T. Rosenkilde, Mette M. Jørgensen, Astrid S.

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