Role of bone marrow Tregs in maintaining stromal cell function

骨髓 Tregs 在维持基质细胞功能中的作用

• 批准号: 10256793
• 负责人: Robert S Welner
• 金额: $ 37.13万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-15 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10256793
• 关键词: Acute Graft Versus Host Disease; Adipose tissue; Autoimmunity; Back; Bone Marrow; Bone Marrow Transplantation; Cell Communication; Cell Differentiation process; Cell Lineage; Cell Maintenance; Cell physiology; Cells; Cellular biology; Characteristics; Communication; Cytokine Receptors; Data; Disease; Disease Progression; Dysmyelopoietic Syndromes; Engraftment; FOXP3 gene; Frequencies; Gene Expression Regulation; Genetic Transcription; Goals; Hematological Disease; Hematopoiesis; Hematopoietic; Hematopoietic Stem Cell Transplantation; Hematopoietic stem cells; Heterogeneity; Homeostasis; Immune; Immune Tolerance; Immune response; Infection; Inflammation; Interleukin-10; Intervention; Lead; Link; Lung; Lymphocyte; Maintenance; Marrow; Mesenchymal Differentiation; Molecular; Molecular Profiling; Mus; Mutation; Outcome; Participant; Peripheral; Play; Precancerous Conditions; Production; Prothrombin; Regulation; Regulatory T-Lymphocyte; Reporter; Reporting; Research; Risk; Role; STAT3 gene; Signal Pathway; Signal Transduction; Skin; Source; Stem cell transplant; Stromal Cells; Supporting Cell; Testing; Tissues; Transplantation; base; bone; cell type; chemokine receptor; conditional knockout; cytokine; experimental study; hematopoietic stem cell quiescence; hematopoietic tissue; improved; leukemia; mesenchymal stromal cell; mouse model; novel; premalignant; prevent; repaired; stem cells; therapeutic target; tissue stem cells

PROJECT SUMMARY / ABSTRACT Regulatory T cells (Tregs) are known for not only their ability to regulate immune response, but also for their heterogeneity and non-canonical functions in tissue maintenance. As recently suggested tissue-specific Tregs have specialized functions to maintain those tissues in which they exist, and in adipose tissue, lung, and skin function to support local tissue stem cells. Accumulating evidence suggests that the stromal microenvironment regulates immune response; we propose that the reverse is also true, specifically through marrow Treg and stromal cell interactions. Interestingly, Tregs represent approximately one-third of all CD4+ T lineage cells in the marrow, a portion that is significantly higher than other hematopoietic tissues; however, the function of tissue resident Tregs in the maintenance of the bone microenvironment and underlying molecular signature remain unclear. Our focus is to uncover the signaling pathways that marrow Treg use to maintain mesenchymal stromal cell's differentiation and hematopoietic stem cells support. We have found that depletion of Tregs alters the bone marrow microenvironment, and more specifically increases cycling and alters differentiation of mesenchymal stromal cells. Based on our preliminary data, we propose that marrow Tregs are a unique subpopulation of immune cells with preferential bias to circulate back to the bone marrow and this is supported by their unique chemokine and cytokine receptor profile. Our research identifies Tregs as the major source of interleukin-10 (IL-10) in the marrow; and support a role for Treg-secreted IL-10 as a main factor that supports stromal cell functions. In ongoing studies, we are trying to define the IL-10 specific mechanisms of stromal cell maintenance. We propose to define how IL-10 signaling pathways in stromal cells support their maintenance (Aim 1). We will characterize the function and transcriptional characteristics of marrow stromal cells using stromal cell fate-mapping mouse models following IL-10 and Treg perturbation to define the molecular drivers for maintenance during hematopoietic stem cell transplants (Aim 2). We expect that these experiments will define new regulatory networks by establishing bi-directional communication between highly specialized tissue-resident lymphocytes and marrow stromal cells. These results will provide the basis for studies to understand how infections, transplantation, or disease may impact these interactions. We will exploit these interactions to impede pre-malignant clones by altering the marrow microenvironment (Aim 3). Moving forward, these findings could lead to therapeutic targets for improved bone marrow transplantation or changing outcomes in hematopoietic disease.

项目概要/摘要 调节性 T 细胞 (Treg) 不仅因其调节免疫反应的能力而闻名，还以其 组织维护中的异质性和非规范功能。正如最近提出的组织特异性 Tregs 具有维持其存在的组织、脂肪组织、肺和皮肤的特殊功能 功能支持局部组织干细胞。越来越多的证据表明基质微环境 调节免疫反应；我们认为反之亦然，特别是通过骨髓 Treg 和 基质细胞相互作用。有趣的是，Treg 细胞约占所有 CD4+ T 谱系细胞的三分之一。 骨髓，明显高于其他造血组织的部分；然而，函数 组织驻留Tregs在维持骨微环境和潜在分子特征中的作用 仍不清楚。我们的重点是揭示骨髓 Treg 用来维持的信号通路 间充质基质细胞的分化和造血干细胞的支持。我们发现耗尽 Tregs 的数量改变了骨髓微环境，更具体地说，增加了循环并改变了 间充质基质细胞的分化。根据我们的初步数据，我们建议骨髓 Tregs 是一种独特的免疫细胞亚群，具有优先循环回骨髓的能力 得到其独特的趋化因子和细胞因子受体谱的支持。我们的研究将 Tregs 确定为 骨髓中白细胞介素 10 (IL-10) 的主要来源；并支持 Treg 分泌的 IL-10 作为主要作用 支持基质细胞功能的因子。在正在进行的研究中，我们正在尝试定义 IL-10 的特异性 基质细胞维持的机制。我们建议定义基质细胞中的 IL-10 信号通路 支持他们的维护（目标 1）。我们将描述其功能和转录特征 骨髓基质细胞使用基质细胞命运图谱小鼠模型，在 IL-10 和 Treg 扰动后 定义造血干细胞移植期间维持的分子驱动因素（目标 2）。我们期望 这些实验将通过建立双向通信来定义新的监管网络 高度专业化的组织驻留淋巴细胞和骨髓基质细胞之间。这些结果将提供 了解感染、移植或疾病如何影响这些相互作用的研究基础。 我们将利用这些相互作用通过改变骨髓微环境来阻止癌前克隆 （目标 3）。展望未来，这些发现可能会导致改善骨髓的治疗目标 移植或改变造血系统疾病的结果。