The adaptive immune system serves as a potent and highly specific defense mechanism against pathogen infection. One component of this system, the effector T cell, facilitates pathogen clearance upon detection of specific antigens by the T cell receptor (TCR). A critical process in effector T cell activation is transmission of signals from the TCR to a key transcriptional regulator, NF-κB. The transmission of this signal involves a highly dynamic process in which helical filaments of Bcl10, a key protein constituent of the TCR signaling cascade, undergo competing processes of polymeric assembly and macroautophagy-dependent degradation. Through computational analysis of three-dimensional super-resolution microscopy data, we quantitatively characterized TCR-stimulated Bcl10 filament assembly and length dynamics, demonstrating that filaments become shorter over time. Additionally, we developed an image-based bootstrap-like resampling method to quantitatively demonstrate preferred association between autophagosomes and Bcl10-filament ends and punctate-Bcl10 structures, implying that autophagosome-driven macroautophagy is directly responsible for Bcl10 filament shortening. We probe Bcl10 polymerization-depolymerization dynamics with a stochastic Monte-Carlo simulation of nucleation-limited filament assembly and degradation, and we show that high probabilities of filament nucleation in response to TCR engagement could provide the observed robust, homogeneous, and tunable response dynamic. Furthermore, the speed of autophagic degradation of filaments preferentially at filament ends provides effective regulatory control. Taken together, these data suggest that Bcl10 filament growth and degradation act as an excitable system that provides a digital response mechanism and the reliable timing critical for T cell activation and regulatory processes.

中文翻译：

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通过聚合和降解进行信号传递：Bcl10介导的T细胞活化的分析和模拟

适应性免疫系统是针对病原体感染的有效且高度特异性的防御机制。该系统的一个组成部分，即效应T细胞，可在T细胞受体（TCR）检测到特定抗原时促进病原体清除。效应器T细胞激活的关键过程是信号从TCR传递到关键的转录调节因子NF-κB。该信号的传输涉及一个高度动态的过程，在该过程中，TCR信号级联反应的关键蛋白质成分Bcl10的螺旋细丝经历了聚合组装和依赖巨噬细胞的降解过程。通过对三维超分辨率显微镜数据的计算分析，我们定量表征了TCR刺激的Bcl10灯丝组件和长度动态，证明细丝会随着时间而变短。此外，我们开发了一种基于图像的类似引导程序的重采样方法，以定量证明自噬体与Bcl10细丝末端和点状Bcl10结构之间的优选关联，这暗示自噬体驱动的宏观自噬是Bcl10细丝缩短的直接原因。我们用成核作用受限的长丝组装和降解的随机蒙特卡洛模拟研究Bcl10聚合-解聚动力学，并且我们发现响应TCR接合的长丝成核的高概率可以提供观察到的鲁棒，均匀和可调的响应动力学。此外，细丝自噬降解的速度优先在细丝末端提供了有效的调节控制。在一起