Single-cell transcriptomics reveals expansion of cytotoxic CD4 T cells in supercentenarians
Single-cell transcriptomics reveals expansion of cytotoxic CD4 T cells in supercentenarians
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DOI：
10.1073/pnas.1907883116
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发表时间：
2019-11-26
影响因子：
11.1
通讯作者：
Carninci, Piero
中科院分区：
文献类型：
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作者：
Hashimoto, Kosuke;Kouno, Tsukasa;Carninci, Piero
超级百岁老人，也就是年龄达到110岁的人，是健康老龄化的典范。他们的特点是与年龄有关的疾病发病时间较晚，发病率较低，这意味着他们的免疫系统仍在发挥作用。在这里，我们对来自7名超级百岁老人和5名年轻对照的61，202个外周血单核细胞（PBMC）进行了单细胞转录组分析。我们确定了细胞毒性CD 4 T细胞（CD 4细胞毒性T淋巴细胞[CTL 5]）的显着增加作为超百岁老人的签名。此外，2名超级百岁老人的单细胞T细胞受体测序显示，CD 4 CTL通过大规模克隆扩增积累，最常见的克隆型占整个CD 4 T细胞群的15%至35%。CD 4 CTL在其细胞毒性程度方面表现出实质性异质性，并且与CD 8 CTL的转录组几乎相同。这表明CD 4 CTL利用CD 8谱系的转录程序，同时保留CD 4表达。事实上，从超级百岁老人中提取的CD 4 CTL产生IFN-γ。和TNF-α。我们的研究表明，超级百岁老人在他们的循环淋巴细胞中具有独特的特征，这可能代表了一种必要的适应，通过维持对感染和疾病的免疫反应来实现非凡的长寿。
Supercentenarians, people who have reached 110 y of age, are a great model of healthy aging. Their characteristics of delayed onset of age-related diseases and compression of morbidity imply that their immune system remains functional. Here we performed single-cell transcriptome analysis of 61,202 peripheral blood mononuclear cells (PBMCs), derived from 7 supercentenarians and 5 younger controls. We identified a marked increase of cytotoxic CD4 T cells (CD4 cytotoxic T lymphocytes [CTL5]) as a signature of supercentenarians. Furthermore, single-cell T cell receptor sequencing of 2 supercentenarians revealed that CD4 CTLs had accumulated through massive clonal expansion, with the most frequent clonotypes accounting for 15 to 35% of the entire CD4 T cell population. The CD4 CTLs exhibited substantial heterogeneity in their degree of cytotoxicity as well as a nearly identical transcriptome to that of CD8 CTLs. This indicates that CD4 CTLs utilize the transcriptional program of the CD8 lineage while retaining CD4 expression. Indeed, CD4 CTLs extracted from supercentenarians produced IFN-gamma. and TNF-alpha upon ex vivo stimulation. Our study reveals that supercentenarians have unique characteristics in their circulating lymphocytes, which may represent an essential adaptation to achieve exceptional longevity by sustaining immune responses to infections and diseases.