Lymphocyte Biology Section, Laboratory of Immune System Biology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892-1892, USA.
Multiscale Systems Biology Section, Laboratory of Immune System Biology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892-1892, USA; Biophysics program, Institute for Physical Science and Technology, University of Maryland, College Park, MD 20742, USA.
Cell. 2021 Jul 22;184(15):3981-3997.e22. doi: 10.1016/j.cell.2021.05.028. Epub 2021 Jun 21.
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.
成熟的 T 细胞有一小部分可被外周自身抗原激活，从而可能引发宿主自身免疫。我们通过结合高分辨率多重和体积成像与计算建模来研究未受干扰的组织环境中自身激活的 T 细胞的动态平衡控制。在淋巴结中，自身激活的 T 细胞产生白细胞介素 (IL)-2，增强了局部调节性 T 细胞 (Treg) 的增殖和抑制功能。由此产生的微区相互限制了有害效应器反应所需的输入，包括 CD28 共刺激和 IL-2 信号，构成了一个负反馈回路。由于这些局部限制，自身激活的 T 细胞经历短暂的克隆扩增，随后迅速死亡（“修剪”）。计算模拟和实验操作揭示了反馈机制的定量限制：Treg 微区密度或功能的适度降低会导致控制的非线性崩溃，从而使自身激活的 T 细胞能够破坏修剪。这种微调的旁分泌反馈过程不仅能维持免疫动态平衡，还能在自身免疫和宿主保护性 T 细胞反应之间建立一个鲜明的边界。
