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: 10428667
• 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/10428667
• 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.

项目摘要 /摘要 调节性T细胞（Tregs）不仅以调节免疫反应的能力，还以其 组织维持中的异质性和非典型功能。最近建议的组织特异性treg 具有专门的功能来维持存在于其存在的组织，以及在脂肪组织，肺和皮肤中 功能以支持局部组织干细胞。积累的证据表明基质微环境 调节免疫反应；我们建议相反的情况也是真实的，特别是通过骨髓Treg和 基质细胞相互作用。有趣的是，Treg代表所有CD4+ T谱系细胞的三分之一 骨髓，一部分明显高于其他造血组织；但是， 在骨微环境和基础分子特征的维持中，组织驻留的tregs 保持不清楚。我们的重点是发现骨髓Treg用于维护的信号传导途径 间充质基质细胞的分化和造血干细胞支持。我们发现耗尽 Tregs改变了骨髓微环境，更具体地增加了循环和改变 间质基质细胞的分化。根据我们的初步数据，我们提出了骨髓tregs 是具有优先偏置的免疫细胞的独特亚群，可以循环回到骨髓，这是 其独特的趋化因子和细胞因子受体谱支持。我们的研究将Tregs确定为 骨髓中白介素10（IL-10）的主要来源；并支持Treg分泌的IL-10作为主要的角色 支持基质细胞功能的因素。在正在进行的研究中，我们试图定义IL-10特定 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）。我们将表征 IL-10之后，使用基质细胞命运小鼠模型和Treg扰动到对 定义造血干细胞移植期间维持的分子驱动因素（AIM 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 在高度专业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的基础。 我们将利用这些相互作用来通过改变骨髓微环境来阻碍临时克隆 （目标3）。向前迈进，这些发现可能导致治疗靶标，以改善骨髓 造血疾病的移植或结果变化。