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DNA origami demonstrate the unique stimulatory power of single pMHCs as T cell antigens [Biophysics and Computational Biology]
Proceedings of the National Academy of Sciences of the United States of America ( IF 9.4 ) Pub Date : 2021-01-26 , DOI: 10.1073/pnas.2016857118
Joschka Hellmeier 1 , Rene Platzer 2 , Alexandra S Eklund 3, 4 , Thomas Schlichthaerle 3, 4 , Andreas Karner 5 , Viktoria Motsch 1 , Magdalena C Schneider 1 , Elke Kurz 6 , Victor Bamieh 1 , Mario Brameshuber 1 , Johannes Preiner 5 , Ralf Jungmann 3, 4 , Hannes Stockinger 2 , Gerhard J Schütz 1 , Johannes B Huppa 2 , Eva Sevcsik 7
Affiliation  

T cells detect with their T cell antigen receptors (TCRs) the presence of rare agonist peptide/MHC complexes (pMHCs) on the surface of antigen-presenting cells (APCs). How extracellular ligand binding triggers intracellular signaling is poorly understood, yet spatial antigen arrangement on the APC surface has been suggested to be a critical factor. To examine this, we engineered a biomimetic interface based on laterally mobile functionalized DNA origami platforms, which allow for nanoscale control over ligand distances without interfering with the cell-intrinsic dynamics of receptor clustering. When targeting TCRs via stably binding monovalent antibody fragments, we found the minimum signaling unit promoting efficient T cell activation to consist of two antibody-ligated TCRs within a distance of 20 nm. In contrast, transiently engaging antigenic pMHCs stimulated T cells robustly as well-isolated entities. These results identify pairs of antibody-bound TCRs as minimal receptor entities for effective TCR triggering yet validate the exceptional stimulatory potency of single isolated pMHC molecules.



中文翻译:


DNA 折纸展示了单个 pMHC 作为 T 细胞抗原的独特刺激能力 [生物物理学和计算生物学]



T 细胞利用其 T 细胞抗原受体 (TCR) 检测抗原呈递细胞 (APC) 表面上稀有激动剂肽/MHC 复合物 (pMHC) 的存在。人们对细胞外配体结合如何触发细胞内信号传导知之甚少,但 APC 表面上的空间抗原排列被认为是一个关键因素。为了研究这一点,我们设计了一个基于横向移动功能化 DNA 折纸平台的仿生界面,该界面允许对配体距离进行纳米级控制,而不干扰受体簇的细胞内在动力学。当通过稳定结合单价抗体片段靶向TCR时,我们发现促进有效T细胞激活的最小信号单元由距离20 nm内的两个抗体连接的TCR组成。相比之下,瞬时接合抗原性 pMHC 会像分离良好的实体一样强烈刺激 T 细胞。这些结果将抗体结合的 TCR 对识别为有效 TCR 触发的最小受体实体,同时验证了单个分离的 pMHC 分子的特殊刺激效力。

更新日期:2021-01-20
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