Nano Lett. 2018 Mar 14;18(3):1916-1924. doi: 10.1021/acs.nanolett.7b05284. Epub 2018 Feb 28.
T cell activation requires the coordination of a variety of signaling molecules including T cell receptor-specific signals and costimulatory signals. Altering the composition and distribution of costimulatory molecules during stimulation greatly affects T cell functionality for applications such as adoptive cell therapy (ACT), but the large diversity in these molecules complicates these studies. Here, we develop and validate a reductionist T cell activation platform that enables streamlined customization of stimulatory conditions. This platform is useful for the optimization of ACT protocols as well as the more general study of immune T cell activation. Rather than decorating particles with both signal 1 antigen and signal 2 costimulus, we use distinct, monospecific, paramagnetic nanoparticles, which are then clustered on the cell surface by a magnetic field. This allows for rapid synthesis and characterization of a small number of single-signal nanoparticles which can be systematically combined to explore and optimize T cell activation. By increasing cognate T cell enrichment and incorporating additional costimulatory molecules using this platform, we find significantly higher frequencies and numbers of cognate T cells stimulated from an endogenous population. The magnetic field-induced association of separate particles thus provides a tool for optimizing T cell activation for adoptive immunotherapy and other immunological studies.
T 细胞的激活需要多种信号分子的协调,包括 T 细胞受体特异性信号和共刺激信号。在刺激过程中改变共刺激分子的组成和分布会极大地影响 T 细胞的功能,例如过继细胞治疗 (ACT),但这些分子的多样性使得这些研究变得复杂。在这里,我们开发并验证了一种简化的 T 细胞激活平台,可实现刺激条件的简化定制。该平台可用于优化 ACT 方案,以及更一般的免疫 T 细胞激活研究。我们没有用信号 1 抗原和信号 2 共刺激物来修饰颗粒,而是使用了独特的、单特异性的顺磁纳米颗粒,然后通过磁场将其在细胞表面聚集。这使得可以快速合成和表征少量的单信号纳米颗粒,然后可以系统地将它们组合起来以探索和优化 T 细胞的激活。通过使用该平台增加同源 T 细胞的富集并结合其他共刺激分子,我们发现从内源性群体中刺激同源 T 细胞的频率和数量显著增加。因此,磁场诱导的单独颗粒的缔合为优化过继免疫治疗和其他免疫研究中的 T 细胞激活提供了一种工具。