Ageing compromises mouse thymus function and remodels epithelial cell differentiation
Ageing compromises mouse thymus function and remodels epithelial cell differentiation
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DOI：
10.7554/elife.56221
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发表时间：
2020-08-25
期刊：
影响因子：
7.7
通讯作者：
Hollander, Georg A.
中科院分区：
文献类型：
--
作者：
Baran-Gale, Jeanette;Morgan, Michael D.;Hollander, Georg A.
衰老的特点是细胞衰老，导致组织维护失衡、细胞死亡和器官功能受损。这首先在胸腺中观察到，胸腺是产生和选择 T 细胞的主要淋巴器官。然而，支撑这些衰老过程的分子和细胞机制仍不清楚。在这里，我们发现小鼠衰老会导致 T 细胞选择效率降低、自身抗原表达减少和 T 细胞受体库多样性增加。通过结合单细胞 RNA 测序和谱系追踪，我们发现祖细胞是衰老的主要目标，而单个成熟胸腺上皮细胞的功能仅受到轻微损害。具体来说，出生后保留在小鼠皮质中的早期生命前体细胞群在青春期实际上消失了。与此同时，髓质前体细胞静止，从而损害髓质上皮的维持。因此，衰老会破坏胸腺祖细胞的分化并损害胸腺的核心免疫功能。
Ageing is characterised by cellular senescence, leading to imbalanced tissue maintenance, cell death and compromised organ function. This is first observed in the thymus, the primary lymphoid organ that generates and selects T cells. However, the molecular and cellular mechanisms underpinning these ageing processes remain unclear. Here, we show that mouse ageing leads to less efficient T cell selection, decreased self-antigen representation and increased T cell receptor repertoire diversity. Using a combination of single-cell RNA-seq and lineage-tracing, we find that progenitor cells are the principal targets of ageing, whereas the function of individual mature thymic epithelial cells is compromised only modestly. Specifically, an early-life precursor cell population, retained in the mouse cortex postnatally, is virtually extinguished at puberty. Concomitantly, a medullary precursor cell quiesces, thereby impairing maintenance of the medullary epithelium. Thus, ageing disrupts thymic progenitor differentiation and impairs the core immunological functions of the thymus.