Shenzhen Guangming District People's Hospital, 4253 Songbai Road, Matian Street, Guangming District, Shenzhen, 518106, Guangdong, China.
Immunol Res. 2024 Oct;72(5):1161-1173. doi: 10.1007/s12026-024-09519-z. Epub 2024 Jul 23.
Age-related thymic involution is characterized by the loss of T cell development and the supporting epithelial network, which are replaced by adipose tissue. We previously showed that aging functionally impairs lymphohematopoietic progenitor cells, including thymic early T cell progenitors (ETPs), contributing to thymic involution. Considering that the thymic microenvironment is essential for thymocyte incubation, we aimed to investigate its role in age-related thymic involution and the mechanisms underlying these changes. The challenge in studying these processes led us to transplant T cell-depleted fetal thymus tissue into the kidney capsule of aged mice. This model allowed us to identify the mechanisms driving age-related changes in the thymic microenvironment and to assess whether these changes could be reversed. Flow cytometry was used to detect naïve T cells (CD62LCD44), including CD4 CD8 double-negative, double-positive, and single-positive T cells. Real-time PCR was used to detect and quantify signal-joint T cell receptor excision circles. We rearranged δRec-ΨJα in murine peripheral blood leukocytes to evaluate the thymic output of newly developed naïve T cells in the mice and gene expression in the thymus. Age-related thymic involution decreased naïve T cells and increased memory T cells, while fetal thymus transplantation improved thymic output and T cell production and reversed the impairment of thymopoiesis due to thymic involution in aged mice. Furthermore, the expression of key cytokines was restored and ETPs in the aged mice showed normal thymic T cell development. Our study suggests that degenerative changes in the thymic microenvironment are the primary cause of thymic dysfunction, leading to immunosenescence associated with age-related thymic involution.
年龄相关性胸腺萎缩的特征是 T 细胞发育和支持上皮网络的丧失，被脂肪组织所取代。我们之前的研究表明，衰老会导致淋巴造血祖细胞功能受损，包括胸腺早期 T 细胞祖细胞（ETP），从而导致胸腺萎缩。考虑到胸腺微环境对胸腺细胞的孵育至关重要，我们旨在研究其在年龄相关性胸腺萎缩中的作用及其潜在机制。研究这些过程的挑战促使我们将 T 细胞耗尽的胎胸腺组织移植到老年小鼠的肾包膜中。该模型使我们能够识别驱动胸腺微环境与年龄相关变化的机制，并评估这些变化是否可以逆转。流式细胞术用于检测幼稚 T 细胞（CD62LCD44），包括 CD4 CD8 双阴性、双阳性和单阳性 T 细胞。实时 PCR 用于检测和量化信号连接 T 细胞受体切除环。我们在小鼠外周血白细胞中重排 δRec-ΨJα，以评估新发育的幼稚 T 细胞在小鼠中的胸腺输出和胸腺中的基因表达。年龄相关性胸腺萎缩会减少幼稚 T 细胞，增加记忆 T 细胞，而胎胸腺移植可改善胸腺输出和 T 细胞生成，并逆转因胸腺萎缩导致的老年小鼠胸腺发育不全。此外，关键细胞因子的表达得到恢复，老年小鼠的 ETP 显示出正常的胸腺 T 细胞发育。我们的研究表明，胸腺微环境的退行性变化是导致胸腺功能障碍的主要原因，导致与年龄相关性胸腺萎缩相关的免疫衰老。
