Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge, UK.
European Molecular Biology Laboratory, European Bioinformatics Institute (EMBL-EBI), Wellcome Genome Campus, Cambridge, UK.
EMBO Rep. 2019 Aug;20(8):e47379. doi: 10.15252/embr.201847379. Epub 2019 Jul 8.
How the age-associated decline of immune function leads to increased cancer incidence is poorly understood. Here, we have characterised the cellular composition of the γδ T-cell pool in peripheral lymph nodes (pLNs) upon ageing. We find that ageing has minimal cell-intrinsic effects on function and global gene expression of γδ T cells, and γδTCR diversity remains stable. However, ageing alters TCRδ chain usage and clonal structure of γδ T-cell subsets. Importantly, IL-17-producing γδ17 T cells dominate the γδ T-cell pool of aged mice-mainly due to the selective expansion of Vγ6 γδ17 T cells and augmented γδ17 polarisation of Vγ4 T cells. Expansion of the γδ17 T-cell compartment is mediated by increased IL-7 expression in the T-cell zone of old mice. In a Lewis lung cancer model, pro-tumourigenic Vγ6 γδ17 T cells are exclusively activated in the tumour-draining LN and their infiltration into the tumour correlates with increased tumour size in aged mice. Thus, upon ageing, substantial compositional changes in γδ T-cell pool in the pLN lead to an unbalanced γδ T-cell response in the tumour that is associated with accelerated tumour growth.
年龄相关的免疫功能下降如何导致癌症发病率增加，目前还了解甚少。在这里，我们研究了外周淋巴结（pLN）中γδ T 细胞库随年龄增长的细胞组成。我们发现，衰老对 γδ T 细胞的功能和整体基因表达仅有最小的细胞内在影响，且 γδTCR 多样性保持稳定。然而，衰老改变了 TCRδ 链的使用和 γδ T 细胞亚群的克隆结构。重要的是，产生 IL-17 的 γδ17 T 细胞主导了老年小鼠的 γδ T 细胞库——主要是由于 Vγ6 γδ17 T 细胞的选择性扩增和 Vγ4 T 细胞 γδ17 极化的增强。γδ17 T 细胞区室的扩张是由老年小鼠 T 细胞区中 IL-7 表达增加介导的。在 Lewis 肺癌模型中，促肿瘤发生的 Vγ6 γδ17 T 细胞仅在肿瘤引流淋巴结中被激活，其浸润肿瘤与老年小鼠中肿瘤体积增加相关。因此，随着年龄的增长，pLN 中 γδ T 细胞库的大量组成变化导致肿瘤中不平衡的 γδ T 细胞反应，从而加速肿瘤生长。
