澳大利亚墨尔本大学Katherine Kedzierska研究组发现，老年人的新生儿和儿童样分子特征源于人类生命周期中T细胞受体(TCR)的变化。这一研究成果发表在2023年9月25日出版的国际学术期刊《自然—免疫学》上。

他们在表型、转录组、克隆和功能水平上定义了四个年龄组针对突出的流感表位HLA-A* 02:01-M158-66 (A2/M158)的CD8+ T细胞免疫。他们确定了从新生儿到儿童再到成人的线性分化轨迹，随后是分化和老年人的克隆重置。老年人的基因图谱与新生儿和儿童的非常相似，尽管在克隆上是不同的。

只有儿童来源和成人来源的A2/M158+CD8+ T细胞具有分化为高细胞毒性表位特异性CD8+ T细胞的潜力，这与高功能公共TCR αβ信号有关。老年人的TCRαβ信号不佳导致肽突变体的增殖、多功能性、贪婪性和识别性降低，尽管没有表现出衰竭的迹象。

这些数据表明，在生命的不同阶段启动T细胞可能会极大地影响CD8+ T细胞对病毒感染的反应。

据了解，CD8+ T细胞提供强大的抗病毒免疫，但表位特异性T细胞如何在人类生命周期中进化尚不清楚。

附：英文原文

Title: Newborn and child-like molecular signatures in older adults stem from TCR shifts across human lifespan

Author: van de Sandt, Carolien E., Nguyen, Thi H. O., Gherardin, Nicholas A., Crawford, Jeremy Chase, Samir, Jerome, Minervina, Anastasia A., Pogorelyy, Mikhail V., Rizzetto, Simone, Szeto, Christopher, Kaur, Jasveen, Ranson, Nicole, Sonda, Sabrina, Harper, Alice, Redmond, Samuel J., McQuilten, Hayley A., Menon, Tejas, Sant, Sneha, Jia, Xiaoxiao, Pedrina, Kate, Karapanagiotidis, Theo, Cain, Natalie, Nicholson, Suellen, Chen, Zhenjun, Lim, Ratana, Clemens, E. Bridie, Eltahla, Auda, La Gruta, Nicole L., Crowe, Jane, Lappas, Martha, Rossjohn, Jamie, Godfrey, Dale I., Thomas, Paul G., Gras, Stephanie, Flanagan, Katie L., Luciani, Fabio, Kedzierska, Katherine

Issue&Volume: 2023-09-25

Abstract: CD8+ T cells provide robust antiviral immunity, but how epitope-specific T cells evolve across the human lifespan is unclear. Here we defined CD8+ T cell immunity directed at the prominent influenza epitope HLA-A*02:01-M158–66 (A2/M158) across four age groups at phenotypic, transcriptomic, clonal and functional levels. We identify a linear differentiation trajectory from newborns to children then adults, followed by divergence and a clonal reset in older adults. Gene profiles in older adults closely resemble those of newborns and children, despite being clonally distinct. Only child-derived and adult-derived A2/M158+CD8+ T cells had the potential to differentiate into highly cytotoxic epitope-specific CD8+ T cells, which was linked to highly functional public T cell receptor (TCR)αβ signatures. Suboptimal TCRαβ signatures in older adults led to less proliferation, polyfunctionality, avidity and recognition of peptide mutants, although displayed no signs of exhaustion. These data suggest that priming T cells at different stages of life might greatly affect CD8+ T cell responses toward viral infections.

DOI: 10.1038/s41590-023-01633-8

Source: https://www.nature.com/articles/s41590-023-01633-8