Department of Physics, Boston University, Boston, MA 02215;
Department of Physics, Boston University, Boston, MA 02215.
Proc Natl Acad Sci U S A. 2021 Jan 5;118(1). doi: 10.1073/pnas.2011709118.
Regulatory T cells (Tregs) play a crucial role in mediating immune response. Yet an algorithmic understanding of the role of Tregs in adaptive immunity remains lacking. Here, we present a biophysically realistic model of Treg-mediated self-tolerance in which Tregs bind to self-antigens and locally inhibit the proliferation of nearby activated T cells. By exploiting a duality between ecological dynamics and constrained optimization, we show that Tregs tile the potential antigen space while simultaneously minimizing the overlap between Treg activation profiles. We find that for sufficiently high Treg diversity, Treg-mediated self-tolerance is robust to fluctuations in self-antigen concentrations but lowering the Treg diversity results in a sharp transition-related to the Gardner transition in perceptrons-to a regime where changes in self-antigen concentrations can result in an autoimmune response. We propose an experimental test of this transition in immune-deficient mice and discuss potential implications for autoimmune diseases.
调节性 T 细胞（Tregs）在调节免疫反应中起着至关重要的作用。然而，Tregs 在适应性免疫中的作用仍然缺乏算法上的理解。在这里，我们提出了一个Treg 介导的自身耐受的生物物理现实模型，其中 Tregs 与自身抗原结合，并在局部抑制附近激活的 T 细胞的增殖。通过利用生态动力学和约束优化之间的对偶性，我们表明 Tregs 在覆盖潜在抗原空间的同时，最大限度地减少 Treg 激活谱之间的重叠。我们发现，对于足够高的 Treg 多样性，Treg 介导的自身耐受对自身抗原浓度的波动具有鲁棒性，但降低 Treg 多样性会导致与感知器中的 Gardner 转变相关的急剧转变——在这种转变中，自身抗原浓度的变化会导致自身免疫反应。我们提出了在免疫缺陷小鼠中对此转变进行实验测试的方案，并讨论了其对自身免疫性疾病的潜在影响。
