近日，美国福瑞德·哈金森癌症研究中心Jarrod A. Dudakov等研究人员合作发现，与年龄相关的上皮缺陷限制胸腺功能和再生。相关论文于2024年8月7日在线发表在《自然—免疫学》杂志上。

研究人员应用单细胞和空间转录组学、谱系追踪及先进成像技术，定义了非造血间质细胞中的年龄相关变化，并发现了两种异常的胸腺上皮细胞（TEC）状态。这些年龄相关TEC（aaTEC）形成了高密度的皮质-髓质边缘上皮簇，这些簇不含胸腺细胞，随着年龄增长而增加，显示出上皮-间充质转化的特征，并与FOXN1的下调相关。

相互作用分析揭示，aaTEC的出现从其他功能性TEC群体中获得了基线信号，充当TEC生长因子的储蓄池。在急性损伤后，aaTEC显著扩张，进一步干扰了营养再生途径，并与退化胸腺的修复缺陷相关。因此，这些发现定义了与免疫老化相关胸腺退化的独特特征，并可能对开发老年人免疫增强疗法具有重要意义。

据悉，胸腺对于建立适应性免疫至关重要，但随着年龄增长会发生退化，导致免疫应答受损。胸腺对急性损伤也极为敏感，尽管具有再生能力，但这一能力随着年龄的增长而下降，原因尚不明确。

附：英文原文

Title: Age-related epithelial defects limit thymic function and regeneration

Author: Kousa, Anastasia I., Jahn, Lorenz, Zhao, Kelin, Flores, Angel E., Acenas, Dante, Lederer, Emma, Argyropoulos, Kimon V., Lemarquis, Andri L., Granadier, David, Cooper, Kirsten, DAndrea, Michael, Sheridan, Julie M., Tsai, Jennifer, Sikkema, Lisa, Lazrak, Amina, Nichols, Katherine, Lee, Nichole, Ghale, Romina, Malard, Florent, Andrlova, Hana, Velardi, Enrico, Youssef, Salma, Burgos da Silva, Marina, Docampo, Melissa, Sharma, Roshan, Mazutis, Linas, Wimmer, Verena C., Rogers, Kelly L., DeWolf, Susan, Gipson, Brianna, Gomes, Antonio L. C., Setty, Manu, Peer, Dana, Hale, Laura, Manley, Nancy R., Gray, Daniel H. D., van den Brink, Marcel R. M., Dudakov, Jarrod A.

Issue&Volume: 2024-08-07

Abstract: The thymus is essential for establishing adaptive immunity yet undergoes age-related involution that leads to compromised immune responsiveness. The thymus is also extremely sensitive to acute insult and although capable of regeneration, this capacity declines with age for unknown reasons. We applied single-cell and spatial transcriptomics, lineage-tracing and advanced imaging to define age-related changes in nonhematopoietic stromal cells and discovered the emergence of two atypical thymic epithelial cell (TEC) states. These age-associated TECs (aaTECs) formed high-density peri-medullary epithelial clusters that were devoid of thymocytes; an accretion of nonproductive thymic tissue that worsened with age, exhibited features of epithelial-to-mesenchymal transition and was associated with downregulation of FOXN1. Interaction analysis revealed that the emergence of aaTECs drew tonic signals from other functional TEC populations at baseline acting as a sink for TEC growth factors. Following acute injury, aaTECs expanded substantially, further perturbing trophic regeneration pathways and correlating with defective repair of the involuted thymus. These findings therefore define a unique feature of thymic involution linked to immune aging and could have implications for developing immune-boosting therapies in older individuals.

DOI: 10.1038/s41590-024-01915-9

Source: https://www.nature.com/articles/s41590-024-01915-9