Age-related thymic involution, leading to reduced T cell production, is one of the major causes of immunosenescence. This results in an increased susceptibility to cancers, infections, and autoimmunity and in reduced vaccine efficacy. Here, we identified that the receptor activator of nuclear factor κB (RANK)–RANK ligand (RANKL) axis in the thymus is altered during aging. Using a conditional transgenic mouse model, we demonstrated that endothelial cells depend on RANK signaling for their cellularity and functional maturation. Decreased RANKL availability during aging resulted in a decline in cellularity and function of both endothelial cells and thymic epithelial cells, contributing to thymic involution. We then found that, whereas RANKL neutralization in young mice mimicked thymic involution, exogenous RANKL treatment in aged mice restored thymic architecture as well as endothelial cell and epithelial cell abundance and functional properties. Consequently, RANKL improved T cell progenitor homing to the thymus and boosted T cell production. This cascade of events resulted in peripheral T cell renewal and effective antitumor and vaccine responses in aged mice. Furthermore, we conducted a proof-of-concept study that showed that RANKL stimulates endothelial cells and epithelial cells in human thymic organocultures. Overall, our findings suggest that targeting the RANK-RANKL axis through exogenous RANKL administration could represent a therapeutic strategy to rejuvenate thymic function and improve T cell immunity during aging.

中文翻译：

---

RANKL 治疗可恢复老年小鼠的胸腺功能并改善 T 细胞介导的免疫反应


与年龄相关的胸腺退化导致 T 细胞生成减少，是免疫衰老的主要原因之一。这导致对癌症、感染和自身免疫的易感性增加，并导致疫苗效力降低。在这里，我们确定胸腺中核因子 κB （RANK）-RANK 配体 （RANKL） 轴的受体激活剂在衰老过程中发生改变。使用条件转基因小鼠模型，我们证明内皮细胞的细胞结构和功能成熟依赖于 RANK 信号传导。衰老过程中 RANKL 可用性降低导致内皮细胞和胸腺上皮细胞的细胞结构和功能下降，导致胸腺退化。然后我们发现，虽然年轻小鼠的 RANKL 中和模拟胸腺退化，但老年小鼠的外源性 RANKL 处理恢复了胸腺结构以及内皮细胞和上皮细胞的丰度和功能特性。因此，RANKL 改善了 T 细胞祖细胞归巢到胸腺并促进了 T 细胞的产生。这一级联事件导致老年小鼠的外周 T 细胞更新和有效的抗肿瘤和疫苗反应。此外，我们进行了一项概念验证研究，表明 RANKL 刺激人胸腺器官培养中的内皮细胞和上皮细胞。总体而言，我们的研究结果表明，通过外源性 RANKL 给药靶向 RANK-RANKL 轴可能代表一种在衰老过程中恢复胸腺功能和提高 T 细胞免疫力的治疗策略。