Department of Applied and Computational Mathematics and Statistics, University of Notre Dame, Notre Dame, Indiana; Biophysics Graduate Program, University of Notre Dame, Notre Dame, Indiana.
Sir William Dunn School of Pathology, University of Oxford, Oxford, UK.
Biophys J. 2022 Nov 1;121(21):4128-4136. doi: 10.1016/j.bpj.2022.09.030. Epub 2022 Sep 30.
T cells are immune cells that continuously scan for foreign-derived antigens on the surfaces of nearly all cells, termed antigen-presenting cells (APCs). They do this by dynamically extending numerous protrusions called microvilli (MVs) that contain T cell receptors toward the APC surface in order to scan for antigens. The number, size, and dynamics of these MVs, and the complex multiscale topography that results, play a yet unknown role in antigen recognition. We develop an anatomically informed model that confines antigen recognition to small areas representing MVs that can dynamically form and dissolve and use the model to study how MV dynamics impact antigen sensitivity and discrimination. We find that MV surveillance reduces antigen sensitivity compared with a completely flat interface, unless MV are stabilized in an antigen-dependent manner, and observe that MVs have only a modest impact on antigen discrimination. The model highlights that MV contacts optimize the competing demands of fast scanning speeds of the APC surface with antigen sensitivity. Our model predicts an interface packing fraction that corresponds closely to those observed experimentally, indicating that T cells operate their MVs near the limits imposed by anatomical and geometric constraints. Finally, we find that observed MV contact lifetimes can be largely influenced by conditions in the T cell/APC interface, with these lifetimes often being longer than the simulation or experimental observation period. This work highlights the role of MVs in antigen recognition.
T 细胞是一种免疫细胞,它会持续扫描几乎所有细胞表面的外来衍生抗原,这些抗原被称为抗原呈递细胞 (APC)。T 细胞通过动态地向 APC 表面伸出许多称为微绒毛 (MV) 的突起来实现这一点,这些突起中包含 T 细胞受体,以便扫描抗原。这些 MV 的数量、大小和动态变化,以及由此产生的复杂多尺度形貌,在抗原识别中起着未知的作用。我们开发了一种解剖学上的模型,将抗原识别限制在可以动态形成和溶解的代表 MV 的小区域内,并利用该模型研究 MV 动力学如何影响抗原的敏感性和辨别能力。我们发现,与完全平坦的界面相比,MV 监测会降低抗原的敏感性,除非 MV 以抗原依赖的方式稳定下来,并且观察到 MV 对抗原的辨别能力只有适度的影响。该模型强调了 MV 接触可以优化 APC 表面快速扫描速度与抗原敏感性之间的竞争需求。我们的模型预测的界面堆积分数与实验观察到的非常接近,这表明 T 细胞在其 MV 附近操作,接近解剖学和几何约束所施加的限制。最后,我们发现观察到的 MV 接触寿命可以在很大程度上受到 T 细胞/APC 界面条件的影响,这些寿命通常比模拟或实验观察期长。这项工作强调了 MV 在抗原识别中的作用。