Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
Department of Pathology and Laboratory Medicine, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
Nat Commun. 2024 Sep 17;15(1):8171. doi: 10.1038/s41467-024-52522-z.
T cell senescence alters the homeostasis of distinct T cell populations and results in decayed adaptive immune protection in older individuals, but a link between aging and dynamic T cell clone changes has not been made. Here, using a newly developed computational framework, Repertoire Functional Units (RFU), we investigate over 6500 publicly available TCR repertoire sequencing samples from multiple human cohorts and identify age-associated RFUs consistently across different cohorts. Quantification of RFU reduction with aging reveals accelerated loss under immunosuppressive conditions. Systematic analysis of age-associated RFUs in clinical samples manifests a potential link between these RFUs and improved clinical outcomes, such as lower ICU admission and reduced risk of complications, during acute viral infections. Finally, patients receiving bone marrow transplantation show a secondary expansion of the age-associated clones upon stem cell transfer from younger donors. Together, our results suggest the existence of a 'TCR clock' that could reflect the immune functions in aging populations.
T 细胞衰老改变了不同 T 细胞群体的体内平衡，导致老年人适应性免疫保护功能衰退，但衰老与动态 T 细胞克隆变化之间的联系尚未建立。在这里，我们使用新开发的计算框架 Repertoire Functional Units (RFU)，研究了来自多个人类队列的 6500 多个公开可用的 TCR 库测序样本，并在不同队列中一致地识别出与年龄相关的 RFU。随着年龄的增长，RFU 减少的定量分析显示在免疫抑制条件下加速丧失。对临床样本中与年龄相关的 RFU 的系统分析表明，这些 RFU 与急性病毒感染期间改善的临床结果（如 ICU 入院率降低和并发症风险降低）之间存在潜在联系。最后，接受骨髓移植的患者在从年轻供体转移干细胞后，会出现与年龄相关的克隆的二次扩增。总之，我们的研究结果表明存在一个“TCR 时钟”，它可以反映衰老人群的免疫功能。
