A fraction of mature T cells can be activated by peripheral self-antigens, potentially eliciting host autoimmunity. We investigated homeostatic control of self-activated T cells within unperturbed tissue environments by combining high-resolution multiplexed and volumetric imaging with computational modeling. In lymph nodes, self-activated T cells produced interleukin (IL)-2, which enhanced local regulatory T cell (Treg) proliferation and inhibitory functionality. The resulting micro-domains reciprocally constrained inputs required for damaging effector responses, including CD28 co-stimulation and IL-2 signaling, constituting a negative feedback circuit. Due to these local constraints, self-activated T cells underwent transient clonal expansion, followed by rapid death (“pruning”). Computational simulations and experimental manipulations revealed the feedback machinery’s quantitative limits: modest reductions in Treg micro-domain density or functionality produced non-linear breakdowns in control, enabling self-activated T cells to subvert pruning. This fine-tuned, paracrine feedback process not only enforces immune homeostasis but also establishes a sharp boundary between autoimmune and host-protective T cell responses.

一部分成熟 T 细胞可以被外周自身抗原激活，可能引发宿主自身免疫。我们通过将高分辨率多重成像和体积成像与计算模型相结合，研究了未受干扰的组织环境中自激活 T 细胞的稳态控制。在淋巴结中，自激活 T 细胞产生白细胞介素 (IL)-2，增强局部调节性 T 细胞 (Treg) 增殖和抑制功能。由此产生的微域相互限制了破坏效应器反应所需的输入，包括 CD28 共刺激和 IL-2 信号传导，构成负反馈电路。由于这些局部限制，自激活 T 细胞经历短暂的克隆扩张，然后快速死亡（“修剪”）。计算模拟和实验操作揭示了反馈机制的定量极限：Treg 微域密度或功能的适度减少会产生控制的非线性故障，从而使自激活 T 细胞能够破坏修剪。这种微调的旁分泌反馈过程不仅能增强免疫稳态，而且在自身免疫和宿主保护性 T 细胞反应之间建立了清晰的界限。