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Distinct conformations of the chemokine receptor CCR4 with implications for its targeting in allergy.

Content Provider	World Health Organization (WHO)-Global Index Medicus
Author	Pease, James E. Lennartz-Walker, Melissa Andrew, David P. Hall, David A. Viney, Jonathan M. Patel, Pallavi Meiser, Andrea Phillips, Rhian M. Cousins, David J. Barton, Nicholas P.
Description	Author Affiliation: Viney JM ( Leukocyte Biology Section, Medical Research Council-Asthma UK Centre in Allergic Mechanisms of Asthma, National Heart and Lung Institute Division, Faculty of Medicine, Imperial College London, London SW7 2AZ, United Kingdom)
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.
ISSN	00221767
e-ISSN	15506606
DOI	10.4049/jimmunol.1300232
Journal	The Journal of Immunology
Issue Number	7
Volume Number	192
Language	English
Publisher	The American Association of Immunologists
Publisher Date	2014-04-01
Publisher Place	United States
Access Restriction	Open
Subject Keyword	Chemotaxis, Leukocyte Immunology Hypersensitivity Receptors, Ccr4 T-lymphocytes Animals Calcium Metabolism Cell Line, Tumor Cell Movement Genetics Chemokine Ccl17 Chemistry Chemokine Ccl22 Endocytosis Flow Cytometry Lymphocyte Activation Mice Models, Molecular Mutation Protein Binding Protein Conformation Protein Structure, Tertiary Research Support, Non-u.s. Gov't Discipline Immunology
Content Type	Text
Resource Type	Article
Subject	Immunology and Allergy Immunology

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Distinct conformations of the chemokine receptor CCR4 with implications for its targeting in allergy.

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Distinct conformations of the chemokine receptor CCR4 with implications for its targeting in allergy.