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。促炎性T细胞，通常称为效应T细胞（TEFF），产生刺激破骨细胞的骨吸收的细胞因子。长期暴露于炎性细胞因子导致骨质疏松症。正常情况下，调节性T细胞TREG抵消TEFF的活性。TREG抑制TEFF，抑制炎症并促进愈合。我们最近发现，破骨细胞可以诱导一类新的Treg，属于CD8谱系。这些被称为TcREG的调节性CD8+ T细胞，像更广泛研究的CD4谱系的TREG一样，也表达转录因子FoxP3。我们已经证明，TcREG可以负调节骨转换和生产的TEFF在小鼠模型绝经后骨质疏松症。破骨细胞从初始CD8 T细胞诱导TcREG，然后负调节破骨细胞的数量和活性，以形成负反馈回路。TcREG可能对维持和恢复骨骼和免疫稳态非常重要。我们建议，在应用程序中研究负反馈回路的机制。我们建议首先揭示破骨细胞诱导CD8 T细胞中FoxP3的机制。这些机制的知识可用于局部诱导TcREG以治疗慢性炎症。第二，额外的实验将揭示TcREG如何负调控破骨细胞。深入了解TcREG如何抑制骨质疏松症中的骨转换可能会导致新的治疗方式，与其他骨侵蚀疾病相关。这种办法将是一种全新的、在机制上与目前使用或开发的办法不同的办法。

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.