Jørgensen Astrid Sissel, Rosenkilde Mette M, Hjortø Gertrud M
Department of Biomedical Sciences, Faculty of Health and Medical Sciences, The Panum Institute, University of Copenhagen, Blegdamsvej 3, DK-2200 Copenhagen, Denmark.
Department of Biomedical Sciences, Faculty of Health and Medical Sciences, The Panum Institute, University of Copenhagen, Blegdamsvej 3, DK-2200 Copenhagen, Denmark.
Gen Comp Endocrinol. 2018 Mar 1;258:4-14. doi: 10.1016/j.ygcen.2017.07.004. Epub 2017 Jul 8.
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.
趋化因子（趋化性细胞因子）及其相关的G蛋白偶联受体（GPCRs）协同作用，以调控免疫细胞在时间和空间上的定位。配体和受体的混杂性，以及趋化因子系统内的偏向性信号传导，增加了基于细胞的免疫系统调控方式的复杂性。偏向性有三种形式：配体偏向、受体偏向和组织偏向。偏向性信号传导在免疫细胞趋化性的精细协调中发挥重要作用，这一点日益得到认可。在本综述中，我们讨论了与CCR7配体偏向和组织偏向信号传导相关的最新发现，并总结了其他趋化因子受体偏向性的已知情况。CCR7由一部分T细胞和成熟树突状细胞（DCs）表达。CCR7与其两种内源性配体CCL19和CCL21一起，在协调成熟抗原呈递DCs与通常在淋巴结（LNs）中发生的初始T细胞之间的相遇中发挥核心作用。CCL21的羧基末端尾巴具有极强的糖胺聚糖（GAG）结合能力。这一过程是启动抗原特异性T细胞介导的免疫反应的先决条件。因此，CCR7及其配体是启动基于细胞的免疫反应的关键参与者。CCL19和CCL21对CCR7表现出不同的相互作用和对接模式，导致不同CCR7构象的稳定，从而优先激活不同的细胞内信号通路（即配体偏向）。一般来说，CCL19似乎产生强烈的瞬时信号，而CCL21产生较弱但更持久的信号。这两种配体的组织差异表达，以及通过DC特异性蛋白酶活性产生第三种配体“无尾CCL21”（组织偏向），协调了DC和T细胞向LN的归巢和启动，每种配体发挥重叠但也不同的作用。
