A Negative Feedback Loop Between Osteoclasts and CD8 T-Cells

描述（由申请人提供）：破骨细胞是人体唯一的骨吸收细胞。促炎t细胞，通常称为效应t细胞（TEFF），产生刺激破骨细胞骨吸收的细胞因子。长期暴露于炎症细胞因子会导致骨质疏松症。正常情况下，调节性t细胞TREG会抵消TEFF的活性。TREG抑制TEFF，抑制炎症，促进愈合。我们最近发现，破骨细胞可以诱导一类新的TREG，属于CD8谱系。这些调节性CD8+ t细胞被称为TcREG，就像CD4谱系中被广泛研究的TREG一样，也表达转录因子FoxP3。我们已经证明，在绝经后骨质疏松症小鼠模型中，TcREG可以负向调节骨转换和TEFF的产生。破骨细胞诱导来自幼稚CD8 t细胞的TcREG，然后CD8 t细胞负调控破骨细胞的数量和活性，形成负反馈循环。TcREG可能对维持和恢复骨骼和免疫稳态非常重要。我们建议，在应用中研究负反馈回路的潜在机制。我们建议首先揭示破骨细胞在CD8 t细胞中诱导FoxP3的机制。了解这些机制可用于局部诱导TcREG治疗慢性炎症。其次，进一步的实验将揭示TcREG如何负向调节破骨细胞。了解TcREG如何抑制骨质疏松症的骨转换可能会导致新的治疗方式，并与其他骨质侵蚀疾病相关。与目前正在使用或开发的方法相比，这种方法将代表一种全新的、机械上独特的途径。

DESCRIPTION (provided by applicant): Osteoclasts are the body's sole bone resorbing cells. Pro-inflammatory T-cells, commonly called effector T-cells (TEFF), produce cytokines that stimulate bone resorption by osteoclasts. Prolonged exposure to the inflammatory cytokines leads to osteoporosis. Normally, regulatory T-cells, TREG, counteract the activity of TEFF. TREG suppress TEFF, suppress inflammation and promote healing. We have recently discovered that osteoclasts can induce a novel class of TREG, belonging to the CD8 lineage. These regulatory CD8+ T-cells, termed TcREG, like the more extensively studied TREG of the CD4 lineage, also express the transcription factor FoxP3. We have demonstrated that TcREG can negatively regulate bone turnover and production of TEFF in a mouse model of postmenopausal osteoporosis. Osteoclasts induce TcREG from naive CD8 T-cells, which then negatively regulate osteoclast numbers and activity, to form a negative feedback loop. TcREG could potentially be very important for maintaining and restoring skeletal and immune homeostasis. We propose, in the application to study the mechanisms underlying the negative feedback loop. We propose to first uncover the mechanism by which osteoclasts induce FoxP3 in CD8 T-cells. Knowledge of these mechanisms could be used to induce TcREG locally to treat chronic inflammation. Second, additional proposed experiments will reveal how TcREG negatively regulate osteoclasts. Insights into how TcREG suppress bone turnover in osteoporosis is likely to lead to new treatment modalities, with relevance to other bone erosion diseases. This approach would represent an entirely new and mechanistically distinct avenue than those currently in use or development.