Mature T cells must distinguish between foreign and self-antigens to promote host defense while limiting autoimmunity. How such discrimination occurs reproducibly has been explored extensively regarding mechanisms regulating initial T cell activation at short time and length scales. Here, we suggest that T cells encounter a higher-level discriminatory boundary post-activation, empowering or constraining their responses over greater spatiotemporal scales. This boundary emerges from coordinated communication among at least three cell types, forming a control system governed by intercellular circuits, including negative feedback from regulatory T cells (Tregs). We propose that the nonlinearities inherent to this system can amplify subtle baseline imbalances in a single cell type’s functional state, altering the threshold for productive T cell responses and autoimmune disease risk.

成熟的 T 细胞必须区分外来抗原和自身抗原，以促进宿主防御，同时限制自身免疫。关于在短时间和长度尺度上调节初始 T 细胞激活的机制，已经广泛探索了这种区分如何可重复发生。在这里，我们建议 T 细胞在激活后遇到更高级别的歧视性边界，在更大的时空尺度上增强或限制它们的反应。该边界来自至少三种细胞类型之间的协调通信，形成由细胞间回路控制的控制系统，包括来自调节性 T 细胞 (Tregs) 的负反馈。我们建议该系统固有的非线性可以放大单个细胞类型功能状态中微妙的基线不平衡，