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Title: Exploring biased agonism at the chemokine receptor CCR4 : implications for targeting in allergic disease
Author: Anderson, Caroline A.
ISNI:       0000 0004 9350 379X
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2017
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The chemokine receptor CCR4 and its ligands CCL17 and CCL22 are strongly implicated in the pathogenesis of allergic diseases, notably asthma. This stems from their involvement in recruiting pro-inflammatory T helper 2 (Th2) cells to inflammatory sites. Targeting CCR4 in allergy, however, is complicated by expression of the receptor on homeostatic T regulatory (T reg) cells. Strategies for selectively targeting CCR4 on Th2 cells are therefore desirable to avoid the development of autoimmune disease. An emerging solution relates to accumulating evidence that CCL17 and CCL22 are functionally selective ligands of their receptor. This thesis therefore examined the hypothesis that CCL17 and CCL22 are biased agonists of CCR4 and induce differential signalling pathways that may be exploited therapeutically. CCR4 expression at the cell surface was found to be strictly regulated in experiments investigating CCR4 turnover, with the receptor undergoing both ligand-induced and constitutive internalization. Importantly, CCR4 was constitutively degraded and replenished at the cell surface by de novo protein synthesis. Truncation of the CCR4 C-terminus by 40 amino acids revealed that this region of CCR4 is important for ligand-induced internalization and chemotaxis. Comparing the chemotactic responsiveness of in vitro-polarized human Th2 cells revealed a lack of redundancy for CCL17 and CCL22. Surprisingly, directional migration of Th2 cells was observed along gradients of CCL22 but not along CCL17 gradients. Conversely, exposure of Th2 cells to CCL17 induced greater adhesion than did exposure to CCL22. Bias at CCR4 was further investigated by comparing the transcriptomes induced in Th2 cells following culture with CCL17 and CCL22. Despite variation between biological replicates, differentially expressed genes were identified that may have implications for T cell activation. Collectively, the data support a model in which CCL22 acts predominantly as a chemoattractant of CCR4+ cells whilst CCL17 plays alternative roles in cell adhesion and retention at inflammatory sites. Fine-tuning CCR4 activity using biased ligands could represent an exciting opportunity for targeting this receptor in allergic diseases.
Supervisor: Pease, James E. Sponsor: Medical Research Council
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral