Local immunoinflammatory events instruct skeletal stem cells (SSCs) to repair/regenerate bone after injury, but mechanisms are incompletely understood. We hypothesized that specialized Regulatory T (Treg) cells are necessary for bone repair and interact directly with SSCs through organ-specific messages. Both in human patients with bone fracture and mouse model of bone injury, we identified a bone injury-responding Treg subpopulation with bone-repair capacity marked by CCR8. Local production of CCL1 induced a massive migration of CCR8+ Treg cells from periphery to the injury site. Depending on secretion of progranulin (PGRN), a protein encoded by the granulin (Grn) gene, CCR8+ Treg cells supported the accumulation and osteogenic differentiation of SSCs, and thereby bone repair. Mechanistically, we revealed that CCL1 enhanced expression level of basic leucine zipper ATF-like transcription factor (BATF) in CCR8+ Treg cells, which bound to Grn promoter and increased Grn translational output and then PGRN secretion. Together, our work provides a new perspective in osteoimmunology and highlights possible ways of manipulating Treg cell signaling to enhance bone repair and regeneration.

中文翻译：

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调节性 T 细胞的前颗粒蛋白依赖性修复功能驱动骨折愈合。


局部免疫炎症事件指示骨骼干细胞 （SSC） 在受伤后修复/再生骨骼，但机制尚不完全清楚。我们假设专门的调节性 T （Treg） 细胞是骨骼修复所必需的，并通过器官特异性信息直接与 SSC 相互作用。在人类骨折患者和骨损伤小鼠模型中，我们鉴定了一个骨损伤反应的 Treg 亚群，其骨修复能力以 CCR8 为标志。CCL1 的局部产生诱导 CCR8 + Treg 细胞从外围大量迁移到损伤部位。根据颗粒蛋白前体 （PGRN） 的分泌，一种由颗粒蛋白 （Grn） 基因编码的蛋白质，CCR8+ Treg 细胞支持 SSC 的积累和成骨分化，从而支持骨修复。从机制上讲，我们揭示了 CCL1 提高了 CCR8 + Treg 细胞中碱性亮氨酸拉链 ATF 样转录因子 （BATF） 的表达水平，该转录因子与 Grn 启动子结合并增加了 Grn 翻译输出，然后增加了 PGRN 分泌。总之，我们的工作为骨免疫学提供了新的视角，并强调了操纵 Treg 细胞信号传导以增强骨骼修复和再生的可能方法。