Biased signaling of G protein-coupled receptors: rom a chemokine receptor CCR7 perspective

Research output: Contribution to journalReviewResearchpeer-review

25 Citations (Scopus)

Abstract

Chemokines (chemotactic cytokines) and their associated G protein-coupled receptors (GPCRs) work in a concerted manner to govern immune cell positioning in time and space. Promiscuity of both ligands and receptors, but also biased signaling within the chemokine system, adds to the complexity of how the cell-based immune system is controlled. Bias comes in three forms; ligand-, receptor- and tissue-bias. Biased signaling is increasingly being recognized as playing an important role in contributing to the fine-tuned coordination of immune cell chemotaxis. In the current review we discuss the recent findings related to ligand- and tissue-biased signaling of CCR7 and summarize what is known about bias at other chemokine receptors. CCR7 is expressed by a subset of T-cells and by mature dendritic cells (DCs). Together with its two endogenous ligands CCL19 and CCL21, of which the carboxy terminal tail of CCL21 displays an extraordinarily strong glycosaminoglycan (GAG) binding, CCR7 plays a central role in coordinating the meeting between mature antigen presenting DCs and naïve T-cells which normally takes place in the lymph nodes (LNs). This process is a prerequisite for the initiation of an antigen-specific T-cell mediated immune response. Thus CCR7 and its ligands are key players in initiating cell-based immune responses. CCL19 and CCL21 display differential interaction- and docking-modes for CCR7 leading to stabilization of different CCR7 conformations and hereby preferential activation of distinct intracellular signaling pathways (i.e. ligand bias). In general CCL19 seems to generate a strong temporal signal, whereas CCL21 generates a weaker, but more persistent signal. Tissue differential expression of these two ligands, and the generation of a third ligand "tailless-CCL21", through DC specific protease activity (tissue bias), orchestrates DC and T-cell LN homing and priming, with each ligand serving overlapping, but also distinct roles.

Original languageEnglish
JournalGeneral and Comparative Endocrinology
Volume258
Issue numberSI
Pages (from-to)4-14
ISSN0016-6480
DOIs
Publication statusPublished - Mar 2018
Event28th Conference of European Comparative Endocrinologists - Leuven, Belgium
Duration: 21 Aug 201625 Aug 2016

Conference

Conference28th Conference of European Comparative Endocrinologists
Country/TerritoryBelgium
CityLeuven
Period21/08/201625/08/2016

Keywords

  • Journal Article
  • Review

Cite this