Molecular characterization of CCR6: Involvement of multiple domains in ligand binding and receptor signaling

Abstract

The CC chemokine receptor 6 (CCR6) is selectively expressed on memory T cells, B cells, and dendritic cells and appears to be involved in the initiation of a memory immune response. The only chemokine ligand for CCR6 is CCL20/MIP-3alpha. In the present study, we attempted to define the extracellular domains (ECDs) of CCR6 responsible for CCL20/MIP-3alpha binding using a domain-swapping approach in which the ECDs of CCR6 were substituted with the corresponding CCR5 domains to generate various CCR6/CCR5 chimeras. These chimeras were tested for receptor expression, ligand binding, and functional activity as evaluated by calcium flux and chemotaxis. All chimeras showed respectable surface expression; however only one, substituted with extracellular loop 1 from CCR5, showed reduced functional activity. The general failure of functionality of the CCR6/CCR5 chimeras may imply that characteristics of each ECD are critical for coordination among all the ECDs of CCR6. Additionally, of interest, a chimera containing all of the ECDs from CCR5 in the context of CCR6 neither responded to CCR5 ligands nor served as a coreceptor for macrophage-tropic HIV-1. These results suggest that not only ECDs but also transmembrane and intracellular domains of CCR5 are involved in both ligand binding and coreceptor activity.

Essential role for CCR6 in certain inflammatory diseases demonstrated using specific antagonist and knockin mice

“…All mAbs substantially reduced cell migration in a dose-dependent manner ( Figure 1G). These results also highlight the importance of the CCR6 N-terminal region in CCL20 binding and signaling, as previously described with chimeric hCCR6 constructs (21). Among the mAbs, h6H12 Fc-KO showed the best inhibition profile.…”

Temporal Proteomics Profiling of Lipid Rafts in CCR6-Activated T Cells Reveals the Integration of Actin Cytoskeleton Dynamics

“…[13][14][15] Despite extensive investigation of the biology of CCR6, little is known about CCR6 signaling. We previously biologically and functionally characterized CCR6; 4,9,10,[16][17][18] in this study, we intended to investigate the molecules dynamically associated with CCR6 signaling.…”

High Sensitive C-Reactive Protein as an Indicator for Pro-Inflammatory Status in Different Degrees of Major Depression

“…[16,17] , whereas their receptors potentiate the immunological functions of macrophages, B cells and helper T cells. [18] Alternatively, the effects of depression on inflammation might be due to its link to psychological stress. For a long time, depressive illness is known to be associated with an increase in several phases of psychological stress as evident by various biochemical tests including the cortisol response test to psychological stressors.…”