A Negative Feedback Loop Between Osteoclasts and CD8 T-Cells

破骨细胞和 CD8 T 细胞之间的负反馈循环

基本信息

批准号：
9060872
负责人：
RAJEEV AURORA
金额：
$ 34.61万
依托单位：
SAINT LOUIS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-04-01 至 2019-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9060872
关键词：
Actins Age Antigen Presentation Antigen-Presenting Cells Antigens Arthritis Autoimmunity Bone Marrow Bone Resorption Buffers CD8B1 gene Cells Chronic Coupled Data Development Disease Elderly Equilibrium Estrogen Replacements Estrogens Exposure to Feedback Forearm Foundations Fracture Healed Hip Fractures Histocompatibility Homeostasis Hormones IL2RA gene Immune Immune response Immune system Immunosuppressive Agents Inflammation Inflammatory Interferons Interleukin-10 Interleukin-6 International Knowledge Lead Lymphocyte Menopause Modality Modeling Morbidity - disease rate Mus Osteitis Osteoblasts Osteoclasts Osteogenesis Osteoporosis Ovariectomy Postmenopausal Osteoporosis Process Production Proteins Regulation Regulatory T-Lymphocyte Rheumatoid Arthritis Role Serum Signal Pathway Signal Transduction Skeletal system T-Cell Receptor T-Lymphocyte TNFSF11 gene Vertebral column Woman activating transcription factor base bisphosphonate bone bone erosion bone loss bone turnover cytokine experience healing in vivo insight men mortality mouse model novel osteoimmunology pathogen prevent public health relevance research study response skeletal transcription factor

项目摘要

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.

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。通常，调节性 T 细胞 TREG 会抵消 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型的TREG，属于CD8谱系。这些调节性 CD8+ T 细胞，称为 TcREG，与更广泛研究的 CD4 谱系的 TREG 一样，也表达转录因子 FoxP3。我们已经证明，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。破骨细胞诱导初始 CD8 T 细胞产生 TcREG，然后负调节破骨细胞数量和活性，形成负反馈循环。 TcREG 对于维持和恢复骨骼和免疫稳态可能非常重要。我们建议，在应用中研究负反馈循环背后的机制。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 来治疗慢性炎症。其次，额外的实验将揭示 TcREG 如何负向调节破骨细胞。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。与目前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。