Centre d'Immunologie de Marseille-Luminy, Aix Marseille Université, INSERM, CNRS, Marseille Cedex 09, France.
Department of Immunology Virology and Inflammation, Cancer Research Center of Lyon (CRCL) UMR INSERM1052, CNRS 5286, Lyon, France.
EMBO Mol Med. 2017 Jun;9(6):835-851. doi: 10.15252/emmm.201607176.
Cytoablative treatments lead to severe damages on thymic epithelial cells (TECs), which result in delayed thymopoiesis and a prolonged period of T-cell immunodeficiency. Understanding the mechanisms that govern thymic regeneration is of paramount interest for the recovery of a functional immune system notably after bone marrow transplantation (BMT). Here, we show that RANK ligand (RANKL) is upregulated in CD4 thymocytes and lymphoid tissue inducer (LTi) cells during the early phase of thymic regeneration. Importantly, whereas RANKL neutralization alters TEC recovery after irradiation, RANKL administration during BMT boosts the regeneration of TEC subsets including thymic epithelial progenitor-enriched cells, thymus homing of lymphoid progenitors, and thymopoiesis. RANKL increases specifically in LTi cells, lymphotoxin α, which is critical for thymic regeneration. RANKL treatment, dependent on lymphotoxin α, is beneficial upon BMT in young and aged individuals. This study thus indicates that RANKL may be clinically useful to improve T-cell function recovery after BMT by controlling multiple facets of thymic regeneration.
细胞消融治疗会导致胸腺上皮细胞（TEC）严重受损，这会导致胸腺生成延迟和 T 细胞免疫缺陷期延长。了解控制胸腺再生的机制对于骨髓移植（BMT）后恢复功能性免疫系统至关重要。在这里，我们表明，在胸腺再生的早期阶段，RANK 配体（RANKL）在 CD4 胸腺细胞和淋巴组织诱导（LTi）细胞中上调。重要的是，虽然 RANKL 中和会改变照射后 TEC 的恢复，但在 BMT 期间给予 RANKL 会促进 TEC 亚群的再生，包括富含胸腺上皮祖细胞的细胞、淋巴祖细胞向胸腺的归巢和胸腺生成。RANKL 特异性增加在 LTi 细胞中，淋巴毒素 α 对于胸腺再生至关重要。RANKL 治疗依赖于淋巴毒素 α，在年轻人和老年人的 BMT 中是有益的。因此，这项研究表明，RANKL 可能具有临床应用价值，可通过控制胸腺再生的多个方面来改善 BMT 后 T 细胞功能的恢复。
