Surface-anchored monomeric agonist pMHCs alone trigger TCR with high sensitivity.
Surface-anchored monomeric agonist pMHCs alone trigger TCR with high sensitivity.
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DOI：
10.1371/journal.pbio.0060043
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发表时间：
2008-02
期刊：
影响因子：
9.8
通讯作者：
Finkel TH
中科院分区：
文献类型：
--
作者：
Ma Z;Sharp KA;Janmey PA;Finkel TH
在 T 细胞和抗原呈递细胞 (APC) 之间的界面，MHC (pMHC) 呈递的肽抗原与 T 细胞受体 (TCR) 结合并启动信号传导。 TCR 信号启动或触发的机制仍不清楚。这个难题的一个有趣的方面是，尽管可溶性激动剂 pMHC 即使在高浓度下也不能触发 TCR，但相同的配体在 APC 表面非常有效地触发 TCR。在这里，我们使用脂质双层或具有确定成分的基于塑料的人工 APC，确定了赋予激动剂 pMHC 如此效力的关键 APC 相关因素。我们发现，在没有任何其他 APC 表面分子的情况下，CD4+ T 细胞是由锚定在流体脂质双层或固定塑料表面上的极少量单体激动剂 pMHC 触发的。重要的是，在双层、塑料表面或真正的 APC 上，内源性 pMHC 不会增强 TCR 触发。然而，TCR 触发很大程度上取决于表面的粘附性和完整的 T 细胞肌动蛋白细胞骨架。基于这些观察，我们提出了 TCR 触发的受体变形模型，以解释 TCR 触发的显着敏感性和特异性。免疫系统的 T 细胞利用 T 细胞受体 (TCR) 作为传感器，不断在淋巴器官中迁移，并探测抗原呈递细胞 (APC) 表面是否存在外来抗原，这是病原体感染的标志。 TCR 与抗原结合导致 T 细胞激活和随后的免疫反应以对抗病原体。有趣的是，尽管 T 细胞对 APC 上的抗原反应良好，但它们不能识别溶液中的相同抗原。是什么使得 APC 上的抗原可被识别？为了解决这个问题，我们使用脂质双层和塑料表面构建具有确定抗原数量、组成和配置的人工 APC。我们发现，T 细胞对人工 APC 上的单个外来抗原很少有反应，并且与目前的一些观点相反，T 细胞识别抗原不需要在 APC 上形成抗原簇。然而，TCR 触发需要 T 细胞粘附到 APC 表面，并且只有在 T 细胞能够移动时才会发生。我们提出，在动态T细胞-APC界面，APC上的抗原通过对TCR施加力并使其结构变形来激活T细胞，这是可溶性抗原由于缺乏锚定而无法实现的。为什么 T 细胞对溶液中的抗原视而不见，但对锚定在表面上的抗原高度敏感？作者表明，这不是由于抗原聚集，而是可能涉及与细胞运动相关的机械力。
At the interface between T cell and antigen-presenting cell (APC), peptide antigen presented by MHC (pMHC) binds to the T cell receptor (TCR) and initiates signaling. The mechanism of TCR signal initiation, or triggering, remains unclear. An interesting aspect of this puzzle is that although soluble agonist pMHCs cannot trigger TCR even at high concentrations, the same ligands trigger TCR very efficiently on the surface of APCs. Here, using lipid bilayers or plastic-based artificial APCs with defined components, we identify the critical APC-associated factors that confer agonist pMHCs with such potency. We found that CD4+ T cells are triggered by very low numbers of monomeric agonist pMHCs anchored on fluid lipid bilayers or fixed plastic surfaces, in the absence of any other APC surface molecules. Importantly, on bilayers, plastic surfaces, or real APCs, endogenous pMHCs did not enhance TCR triggering. TCR triggering, however, critically depended upon the adhesiveness of the surface and an intact T cell actin cytoskeleton. Based on these observations, we propose the receptor deformation model of TCR triggering to explain the remarkable sensitivity and specificity of TCR triggering. Using the T cell receptor (TCR) as a sensor, T cells of the immune system constantly migrate in lymphoid organs and probe the surface of antigen-presenting cells (APCs) for foreign antigens, a sign of pathogen infection. Antigen binding by TCRs leads to T cell activation and subsequent immune response to combat the pathogens. Interestingly, although T cells respond well to antigens on APCs, they do not recognize the same antigens in solution. What is it that makes antigens on APCs recognizable? To address this, we used lipid bilayers and plastic surfaces to construct artificial APCs with defined antigen number, composition, and configuration. We found that T cells respond to very few individual foreign antigens on artificial APCs, and contrary to some current opinion, formation of antigen clusters on APCs is not required for antigen recognition by T cells. TCR triggering, however, requires T cell adhesion to the APC surface and then occurs only if the T cells are able to move. We propose that at the dynamic T cell–APC interface, antigen on APCs activates T cells by applying force to the TCR and deforming its structure, which cannot be achieved by soluble antigens due to their lack of anchorage. Why is it that T cells are blind to antigens in solution but highly sensitive to antigens anchored on a surface? The authors show that this is not due to antigen clustering, but could involve mechanical forces associated with cell locomotion.
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