Basic Immunology Laboratory, Research Institute, Nozaki Tokushukai Hospital, Tanigawa, Daito, Osaka, Japan.
Single Molecule Imaging, WPI Immunology Frontier Research Center, Osaka University, Furuedai, Suita, Osaka, Japan.
Int Immunol. 2019 Oct 16;31(11):743-753. doi: 10.1093/intimm/dxz043.
The immune system in tolerance maintains cell diversity without responding to self-antigens. Foxp3-expressing CD25+CD4+ regulatory T cells (Tregs) inhibit T-cell activation through various molecular mechanisms. However, several key questions are still not resolved, including how Tregs control the immune response on the basis of their self-skewed T-cell receptor repertoire and how Tregs avoid impeding relevant immunity against pathogens. Here, we show that Tregs promote the proliferation of conventional T cells in the presence of excessive co-stimulation when murine T cells are stimulated in vitro with allogeneic antigen-presenting cells (APCs). Antigen-specific Tregs increase the number of cells interacting with dendritic cells (DCs) by increasing the number of viable DCs and the expression of adhesion molecules on DCs. Theoretical simulations and mathematical models representing the dynamics of T-APC interaction and T-cell numbers in a lymph node indicate that Tregs reduce the dissociation probability of T cells from APCs and increase the new association. These functions contribute to tolerance by enhancing the interaction of low-affinity T cells with APCs. Supporting the theoretical analyses, we found that reducing the T-cell numbers in mice increases the ratio of specific T cells among CD4+ T cells after immunization and effectively induces autoimmune diabetes in non obese diabetes mice. Thus, as a critical function, antigen-specific Tregs stabilize the immune state, irrespective of it being tolerant or responsive, by augmenting T-APC interaction. We propose a novel regulation model in which stable tolerance with large heterogeneous populations proceeds to a specific immune response through a transient state with few populations.
在耐受状态下，免疫系统维持着细胞多样性，而不对自身抗原产生反应。Foxp3 表达的 CD25+CD4+调节性 T 细胞（Tregs）通过多种分子机制抑制 T 细胞的激活。然而，仍有几个关键问题尚未解决，包括 Tregs 如何基于其自身偏向的 T 细胞受体库来控制免疫反应，以及 Tregs 如何避免阻碍针对病原体的相关免疫。在这里，我们表明，在体外使用同种异体抗原呈递细胞（APCs）刺激小鼠 T 细胞时，Tregs 在存在过度共刺激的情况下促进常规 T 细胞的增殖。抗原特异性 Tregs 通过增加存活的 DC 数量和 DC 上黏附分子的表达，增加与树突状细胞（DC）相互作用的细胞数量，从而增加了与 DC 相互作用的细胞数量。代表 T-APC 相互作用和淋巴结中 T 细胞数量动态的理论模拟和数学模型表明，Tregs 降低了 T 细胞与 APC 解离的概率，并增加了新的结合。这些功能通过增强低亲和力 T 细胞与 APC 的相互作用，有助于耐受。为了支持理论分析，我们发现，在免疫后减少小鼠中的 T 细胞数量会增加 CD4+T 细胞中特异性 T 细胞的比例，并有效地在非肥胖糖尿病小鼠中诱导自身免疫性糖尿病。因此，作为一种关键功能，抗原特异性 Tregs 通过增强 T-APC 相互作用，稳定了免疫状态，无论其是耐受还是有反应。我们提出了一个新的调控模型，即通过一个种群较少的短暂状态，从具有大异质种群的稳定耐受转变为特定免疫反应。
