A diverse T cell receptor (TCR) repertoire is essential for protection against a variety of pathogens, and TCR repertoire size is believed to decline with age. However, the precise size of human TCR repertoires, in both total and subsets of T cells, as well as their changes with age, are not fully characterized. We conducted a longitudinal analysis of the human blood TCRα and TCRβ repertoire of CD4⁺ and CD8⁺ T cell subsets using a unique molecular identifier–based (UMI-based) RNA-seq method. Thorough analysis of 1.9 × 10⁸ T cells yielded the lower estimate of TCR repertoire richness in an adult at 3.8 × 10⁸. Alterations of the TCR repertoire with age were observed in all 4 subsets of T cells. The greatest reduction was observed in naive CD8⁺ T cells, while the greatest clonal expansion was in memory CD8⁺ T cells, and the highest increased retention of TCR sequences was in memory CD8⁺ T cells. Our results demonstrated that age-related TCR repertoire attrition is subset specific and more profound for CD8⁺ than CD4⁺ T cells, suggesting that aging has a more profound effect on cytotoxic as opposed to helper T cell functions. This may explain the increased susceptibility of older adults to novel infections.

中文翻译：

---

纵向分析揭示了人类 T 细胞亚群的 T 细胞受体库中与年龄相关的变化

多样化的 T 细胞受体 (TCR) 库对于保护免受多种病原体的侵害至关重要，并且 TCR 库的大小被认为会随着年龄的增长而下降。然而，人类 TCR 库的精确大小，包括 T 细胞的总数和亚群，以及它们随年龄的变化，还没有完全表征。我们使用基于独特分子标识符（基于 UMI）的 RNA-seq 方法对 CD4 ⁺和 CD8 ⁺ T 细胞亚群的人血 TCRα 和 TCRβ 库进行了纵向分析。对 1.9 × 10 ^{8 T 细胞的全面分析得出了 3.8 × 10 8}成人 TCR 库丰富度的较低估计值. 在所有 4 个 T 细胞亚群中观察到 TCR 库随年龄的变化。在初始 CD8 ⁺ T 细胞中观察到最大的减少，而最大的克隆扩增在记忆 CD8 ⁺ T 细胞中，而 TCR 序列的最高增加保留在记忆 CD8 ⁺ T 细胞中。我们的研究结果表明，与年龄相关的 TCR 曲目损耗对 CD8 + T 细胞具有亚群特异性且^比CD4 ⁺ T 细胞更深远，这表明与辅助 T 细胞功能相比，衰老对细胞毒性的影响更深远。这可以解释老年人对新型感染的易感性增加。