从-MHC结合中分离T细胞受体信号的结构机制
Leah V Sibener1, Ricardo A Fernandes2, Elizabeth M Kolawole3
1Departments of Molecular and Cellular Physiology and Structural Biology, Stanford University School of Medicine, Stanford, CA 94305, USA; Immunology Graduate Program, Stanford University School of Medicine, Stanford, CA 94305, USA.
Cell
|July 28, 2018
概括
高亲和性T细胞受体 (TCR) 与-MHC (pMHC) 的相互作用可能是非刺激性的. 这项研究揭示了激活TCR-pMHC相互作用的"捕获键",这对于T细胞信号传递和免疫治疗至关重要.
科学领域:
- 免疫学
- 生物物理
- 结构生物学
背景情况:
- T细胞受体 (TCR) 信号强度通常与-MHC (pMHC) 结合亲和力相关.
- 然而,在人类T细胞中经常观察到不导致T细胞激活的高 afinity TCR- pMHC相互作用.
研究的目的:
- 尽管具有强大的pMHC结合,但对激活具有耐火性的TCRs背后的分子机制的研究.
- 确定控制TCR与T细胞信号结合的新参数.
主要方法:
- 酵母pMHC显示器用于识别TCR激动剂.
- 单分子力测量 (SMFM) 用于分析TCR-pMHC相互作用.
- 分子动力学 (MD) 模拟以模拟TCR-pMHC脱动力学.
主要成果:
- 对3D亲和度,2D停留时间和晶体结构的分析不能完全解释刺激性和非刺激性TCR- pMHC相互作用之间的差异.
- 在激活TCR- pMHC相互作用时发现了捕获键的出现,与接触部位的CD45排除相关.
- 通过在TCR- pMHC接口上获得捕获键,MD模拟区分了激素与非激素配体.
结论:
- 捕获债券代表了关键参数,将TCR结合亲缘关系与信号结果联系起来.
- 了解捕获链接为免疫疗法开发中的TCR和抗原工程提供了新的途径.
- 这一发现促进了对T细胞激活和免疫反应调节的机制理解.
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