淋巴细胞生物学组Ronald N. Germain研究团队揭示了抑制性PD-1轴维持高亲和性干细胞样CD8⁺ T细胞。相关论文于2025年11月26日发表在《自然》杂志上。

利用先进的三维多重免疫荧光成像技术，研究人员在肿瘤引流淋巴结中发现了支持TCF-1⁺PD-1⁺ SLAMF6^high干细胞样CD8⁺ T细胞扩增、维持和亲和力进化的抗原呈递龛。与持续T细胞受体（TCR）信号传导驱动终端效应分化的普遍观点相反，超过初始启动的抗原接合时间延长阻碍了这些干细胞样T细胞在体内的增殖和自我更新。抑制性PD-1通路通过微调TCR信号输入，在这一过程中发挥核心作用，使高亲和的TCR茎样克隆作为效应细胞的可再生载体选择性扩增。PD-1阻断会破坏这种调节，导致最强烈的抗肿瘤干细胞的最终分化或死亡。因此，他们的研究结果揭示了TCR配体亲和力识别、一个关键的负反馈调节回路和T细胞干细胞编程之间的关系。

此外，这些发现提出了一个问题，即在癌症免疫治疗期间，抗PD-1阻断是否能提供短期的抗肿瘤作用，但代价是由于这些关键的高亲和力前体的逐渐丧失而降低了疗效。

据介绍，干细胞样祖细胞是自我更新的细胞毒性T细胞，在成功的检查点免疫治疗过程中作为效应细胞扩增。新出现的证据表明，肿瘤引流淋巴结支持这些干细胞样细胞的持续产生，这些干细胞样细胞补充肿瘤部位，并且是扩大效应群的关键来源，这强调了了解促进和维持激活T细胞处于干细胞样状态的因素的重要性。

附：英文原文

Title: Inhibitory PD-1 axis maintains high-avidity stem-like CD8+ T cells

Author: Hor, Jyh Liang, Schrom, Edward C., Wong-Rolle, Abigail, Vistain, Luke, Shang, Wanjing, Dong, Qiang, Zhao, Chen, Jin, Chengcheng, Germain, Ronald N.

Issue&Volume: 2025-11-26

Abstract: Stem-like progenitors are self-renewing cytotoxic T cells that expand as effector cells during successful checkpoint immunotherapy1,2. Emerging evidence suggests that tumour-draining lymph nodes support the continuous generation of these stem-like cells that replenish tumour sites and are a key source of expanded effector populations3,4,5,6, underlining the importance of understanding what factors promote and maintain activated T cells in the stem-like state. Here, using advanced three-dimensional multiplex immunofluorescence imaging, we identify antigen-presentation niches in tumour-draining lymph nodes that support the expansion, maintenance and affinity evolution of TCF-1+PD-1+SLAMF6high stem-like CD8+ T cells. Contrary to the prevailing view that persistent T cell receptor (TCR) signalling drives terminal effector differentiation, prolonged antigen engagement days beyond initial priming sustains the proliferation and self-renewal of these stem-like T cells in vivo. The inhibitory PD-1 pathway has a central role in this process through fine-tuning the TCR signal input that enables the selective expansion of high-affinity TCR stem-like clones as a renewable source of effector cells. PD-1 blockade disrupts this tuning, leading to terminal differentiation or death of the most avid anti-tumour stem-like cells. Our results therefore reveal a relationship between TCR ligand affinity recognition, a key negative-feedback regulatory loop and T cell stemness programming. Furthermore, these findings raise questions about whether anti-PD-1 blockade during cancer immunotherapy provides a short-term anti-tumour effect at the cost of diminishing efficacy due to progressive loss of these critical high-affinity precursors.

DOI: 10.1038/s41586-025-09440-x

Source: https://www.nature.com/articles/s41586-025-09440-x