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Title: Distinct conformations of the chemokine receptor CCR4 with implications for its targeting in allergy
Authors: Viney, Jonathan M.
Phillips, Rhian M.
Meiser, Andrea
Patel, Pallavi
Pease, James E.
Andrew, David P.
Barton, Nicholas P.
Hall, David A.
Lennartz-Walker, Melissa
Cousins, David J.
First Published: 21-Feb-2014
Publisher: American Association of Immunologists
Citation: Journal of Immunology, 2014, 192 (7), pp. 3419-3427
Abstract: CC chemokine receptor 4 (CCR4) is expressed by Th2 and regulatory T cells and directs their migration along gradients of the chemokines CCL17 and CCL22. Both chemokines and receptor are upregulated in allergic disease, making CCR4 a therapeutic target for the treatment of allergy. We set out to assess the mechanisms underlying a previous report that CCL22 is a dominant ligand of CCR4, which may have implications for its therapeutic targeting. Human T cells expressing endogenous CCR4 and transfectants engineered to express CCR4 were assessed for receptor function, using assays of calcium release, chemotaxis, receptor endocytosis, and ligand binding. Despite the two ligands having equal potency in calcium flux and chemotaxis assays, CCL22 showed dominance in both receptor endocytosis assays and heterologous competitive binding assays. Using two different CCR4-specific Abs, we showed that CCR4 exists in at least two distinct conformations, which are differentially activated by ligand. A major population is activated by both CCL17 and CCL22, whereas a minor population is activated only by CCL22. Mutation of a single C-terminal residue K310 within a putative CCR4 antagonist binding site ablated activation of CCR4 by CCL17, but not by CCL22, despite having no effect on the binding of either ligand. We conclude that CCL17 and CCL22 are conformationally selective ligands of CCR4 and interact with the receptor by substantially different mechanisms. This finding suggests that the selective blockade of CCR4 in allergy may be feasible when one CCR4 ligand dominates, allowing the inhibition of Th2 signaling via one ligand while sparing regulatory T cell recruitment via another. The Journal of Immunology, 2014, 192: 3419-3427. © Copyright 2014 by The American Association of Immunologists, Inc. All rights reserved.
DOI Link: 10.4049/jimmunol.1300232
ISSN: 0022-1767
eISSN: 1550-6606
Embargo on file until: 1-Jan-10000
Type: Journal Article
Rights: Copyright © 2014 by The American Association of Immunologists, Inc. All rights reserved.
Description: Full text of this item is not currently available on the LRA. The final published version may be available through the links above.
Appears in Collections:Published Articles, Dept. of Infection, Immunity and Inflammation

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