Department of Microbiology and Abramson Family Cancer Research Institute, University of Pennsylvania, Philadelphia, PA 19104, USA.
Proc Natl Acad Sci U S A. 2013 Jul 2;110(27):E2480-9. doi: 10.1073/pnas.1305394110. Epub 2013 Apr 22.
High surface expression of programmed death 1 (PD-1) is associated with T-cell exhaustion; however, the relationship between PD-1 expression and T-cell dysfunction has not been delineated. We developed a model to study PD-1 signaling in primary human T cells to study how PD-1 expression affected T-cell function. By determining the number of T-cell receptor/peptide-MHC complexes needed to initiate a Ca(2+) flux, we found that PD-1 ligation dramatically shifts the dose-response curve, making T cells much less sensitive to T-cell receptor-generated signals. Importantly, other T-cell functions were differentially sensitive to PD-1 expression. We observed that high levels of PD-1 expression were required to inhibit macrophage inflammatory protein 1 beta production, lower levels were required to block cytotoxicity and IFN-γ production, and very low levels of PD-1 expression could inhibit TNF-α and IL-2 production as well as T-cell expansion. These findings provide insight into the role of PD-1 expression in enforcing T-cell exhaustion and the therapeutic potential of PD-1 blockade.
程序性死亡受体 1（PD-1）的高表面表达与 T 细胞耗竭有关；然而，PD-1 表达与 T 细胞功能障碍之间的关系尚未阐明。我们建立了一个模型来研究原发性人 T 细胞中的 PD-1 信号转导，以研究 PD-1 表达如何影响 T 细胞功能。通过确定启动 Ca(2+)流所需的 T 细胞受体/肽 MHC 复合物的数量，我们发现 PD-1 配体显著改变了剂量反应曲线，使 T 细胞对 T 细胞受体产生的信号的敏感性降低。重要的是，其他 T 细胞功能对 PD-1 表达的敏感性不同。我们观察到，抑制巨噬细胞炎症蛋白 1β的产生需要高水平的 PD-1 表达，阻断细胞毒性和 IFN-γ产生需要较低水平的 PD-1 表达，而非常低水平的 PD-1 表达也可以抑制 TNF-α和 IL-2 的产生以及 T 细胞的扩增。这些发现为 PD-1 表达在强制 T 细胞耗竭中的作用以及 PD-1 阻断的治疗潜力提供了深入的了解。
