Role of bone marrow Tregs in maintaining stromal cell function

项目摘要/摘要 调节性T细胞(Treg)不仅以其调节免疫反应的能力而闻名，而且因其 组织维持中的异质性和非典范功能。正如最近提出的组织特异性Tregs 有特殊的功能来维持它们所在的组织，以及脂肪组织、肺和皮肤 支持局部组织干细胞的功能。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 基质细胞的相互作用。有趣的是，Tregs约占所有CD4+T细胞的三分之一 骨髓，这一部分明显高于其他造血组织；然而， 组织驻留树在维持骨微环境和潜在分子特征中的作用 目前仍不清楚。我们的重点是发现骨髓Treg用来维持 间充质基质细胞的分化和造血干细胞的支持。我们已经发现这种耗尽 改变骨髓微环境，更具体地说，增加循环和改变 间充质基质细胞的分化。根据我们的初步数据，我们认为骨髓树 是一种独特的免疫细胞亚群，具有优先循环回骨髓的倾向 是由他们独特的趋化因子和细胞因子受体图谱支持的。我们的研究发现特雷格斯是 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 支持基质细胞功能的因子。在正在进行的研究中，我们正试图定义IL-10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 支持其维护(目标1)。我们将描述它的功能和转录特征。 骨髓基质细胞在IL-10和Treg扰动后使用基质细胞命运映射小鼠模型 确定在造血干细胞移植过程中维持的分子驱动因素(目标2)。我们预计 这些实验将通过建立双向通信来定义新的监管网络 在高度专门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 这是研究了解感染、移植或疾病如何影响这些相互作用的基础。 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，这些发现可能导致改善骨髓的治疗目标。 移植或改变血液系统疾病的结果。

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.