A computational study of co-inhibitory immune complex assembly at the interface between T cells and antigen presenting cells.
A computational study of co-inhibitory immune complex assembly at the interface between T cells and antigen presenting cells.
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在T细胞和抗原呈递细胞之间的界面处的共抑制免疫复合物组装的计算研究。
DOI：
10.1371/journal.pcbi.1008825
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发表时间：
2021-03
影响因子：
4.3
通讯作者：
Wu Y
中科院分区：
文献类型：
--
作者：
Su Z;Dhusia K;Wu Y
T细胞的活化和分化主要直接由其共调节受体调控。T淋巴细胞相关蛋白 - 4（CTLA - 4）和程序性细胞死亡 - 1（PD - 1）是两种最重要的共调节受体。PD - 1和CTLA - 4与它们在抗原呈递细胞（APC）上相应的配体程序性细胞死亡配体1（PD - L1）和B7结合，激活两条主要的共抑制信号通路以抑制T细胞功能。有趣的是，近期实验发现了PD - L1和B7之间一种新的顺式相互作用，这表明两个共抑制受体之间存在串扰，并且这两对配体 - 受体复合物能够进行动态寡聚化。受这些实验证据的启发，我们开发了一个粗粒度模型来描述由CLTA - 4、B7、PD - L1和PD - 1组成的免疫复合物的组装。这四种蛋白质及其相互作用形成了一个小的网络基序。通过扩散 - 反应算法模拟了该网络的时间动态和空间模式形成。我们的模拟方法考虑了细胞表面蛋白质的膜限制以及这些蛋白质之间不同结合界面的几何排列。对网络中涉及的相互作用测试了多种结合常数。有趣的是，我们发现CTLA - 4/B7配体 - 受体复合物能够首先形成线性寡聚体，然后这些寡聚体进一步排列在一起形成二维簇。在其他细胞表面蛋白质系统中也观察到了类似现象。我们的测试结果进一步表明，由B7和PD - L1激活的两条共抑制信号通路都能够被这两种配体之间新的顺式相互作用下调，这与之前的实验证据相符。最后，模拟还表明免疫复合物组装的动态和空间特性在很大程度上由网络中分子相互作用的能量学决定。因此，我们的研究为T细胞活化的共调节机制带来了新的见解。
T细胞的活化可由其表面的受体如CTLA - 4和PD - 1调控。人们过去认为这两种受体通过不同的途径抑制T细胞活化。然而，近期实验发现这两种受体的配体B7和PD - L1能够在抗原呈递细胞的同一表面相互作用。在此我们利用计算机模拟来研究这种新发现的相互作用在T细胞共调节中的功能作用。我们的模型考虑了T细胞和抗原呈递细胞之间界面的特定环境。配体和受体在这个界面区域内随机扩散。它们进一步参与不同类型的相互作用，包括在细胞表面同侧或对侧的相互作用。利用这种方法，我们发现配体和受体不仅能够形成复合物，还能够聚集成大规模的簇。我们还证明了B7和PD - L1之间的结合能够减少它们与相应受体的相互作用。因此，这项研究为我们理解T细胞中的信号调节提供了新的见解。
The activation and differentiation of T-cells are mainly directly by their co-regulatory receptors. T lymphocyte-associated protein-4 (CTLA-4) and programed cell death-1 (PD-1) are two of the most important co-regulatory receptors. Binding of PD-1 and CTLA-4 with their corresponding ligands programed cell death-ligand 1 (PD-L1) and B7 on the antigen presenting cells (APC) activates two central co-inhibitory signaling pathways to suppress T cell functions. Interestingly, recent experiments have identified a new cis-interaction between PD-L1 and B7, suggesting that a crosstalk exists between two co-inhibitory receptors and the two pairs of ligand-receptor complexes can undergo dynamic oligomerization. Inspired by these experimental evidences, we developed a coarse-grained model to characterize the assembling of an immune complex consisting of CLTA-4, B7, PD-L1 and PD-1. These four proteins and their interactions form a small network motif. The temporal dynamics and spatial pattern formation of this network was simulated by a diffusion-reaction algorithm. Our simulation method incorporates the membrane confinement of cell surface proteins and geometric arrangement of different binding interfaces between these proteins. A wide range of binding constants was tested for the interactions involved in the network. Interestingly, we show that the CTLA-4/B7 ligand-receptor complexes can first form linear oligomers, while these oligomers further align together into two-dimensional clusters. Similar phenomenon has also been observed in other systems of cell surface proteins. Our test results further indicate that both co-inhibitory signaling pathways activated by B7 and PD-L1 can be down-regulated by the new cis-interaction between these two ligands, consistent with previous experimental evidences. Finally, the simulations also suggest that the dynamic and the spatial properties of the immune complex assembly are highly determined by the energetics of molecular interactions in the network. Our study, therefore, brings new insights to the co-regulatory mechanisms of T cell activation. The activation of a T cell can be regulated by the receptors on its surface, such as CTLA-4 and PD-1. People used to think that these two receptors inhibit T cell activation through distinct pathways. However, recent experiments discovered that the ligands of these two receptors, B7 and PD-L1, can interact with each other on the same surface of antigen presenting cells. Here we utilized computational simulations to investigate functional roles of this newly discovered interaction in T cell coregulation. The specific environment of interface between T cell and antigen presenting cell has been taken into account of our model. Ligand and receptors randomly diffuse within this interface area. They further involve in different types of interactions, with each other from the same side or the opposite side of cell surface. Using this method, we found ligands and receptors can not only form complexes, but also aggregate into large-scale clusters. We also demonstrated that the engagement between B7 and PD-L1 can reduce the interactions with their corresponding receptors. This study, therefore, offers new insights to our understanding of signal regulation in T cells.
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T细胞共刺激和共抑制的分子机制。
DOI：
10.1038/nri3405
发表时间：
2013-04
期刊：
Nature reviews. Immunology
影响因子：
--
作者：
通讯作者：
--
免疫调节配体的B7家族。
影响因子：
12.3
作者：
Collins, Mary;Ling, Vincent;Carreno, Beatriz M
通讯作者：
Carreno, Beatriz M
影响因子：
5.5
作者：
Dhusia, Kalyani;Su, Zhaoqian;Wu, Yinghao
通讯作者：
Wu, Yinghao
影响因子：
2
作者：
Andrews, SS;Bray, D
通讯作者：
Bray, D
影响因子：
3.6
作者：
Huang J;Meyer C;Zhu C
通讯作者：
Zhu C