control of Inflammation by regulatory T cells and BCL6

描述(申请人提供)：调节性T细胞(T-reg细胞)，表达转录因子FOXP3，代表一个独特的辅助T细胞谱系，对于维持免疫动态平衡和抑制自身免疫性疾病是不可或缺的。因此，了解这一重要T细胞亚群的表型、功能和调节，对于开发成功的治疗自身免疫病理的方法特别有必要。转录抑制因子BCL6调节免疫系统的几个关键途径，并在B细胞中扮演癌基因的角色。Bcl6是T细胞命运的主要仲裁者，然而，人们对BCL6在T-reg细胞中的作用知之甚少。Bcl6缺陷小鼠(BKO小鼠)患上严重的炎症性疾病，类似于在已知T-reg缺陷小鼠中观察到的疾病，尽管这种疾病主要限于心脏和肺。这种炎症是自发的，大多数小鼠在出生几周后就会患上这种疾病，小鼠总是在很小的时候就死亡。在BKO小鼠中需要T细胞来调节炎症，这表明这种疾病有自身免疫成分。由于T-reg细胞通过防止效应器T细胞反应引起侧枝损伤和控制炎症而参与维持免疫动态平衡，T-reg功能的紊乱为BKO小鼠的炎症性疾病提供了可能的解释。我们的初步结果表明，BKO T-reg细胞的Th2基因水平升高和microRNA谱改变，可能会损害它们阻断心脏和肺特异性炎症的能力。因此，我们假设BCL6在调节T-reg功能方面具有关键作用，特别是通过在体内Th2型炎症环境中稳定T-reg表型。这种稳定性如何与BCL6在抑制T-reg细胞中Th2基因表达的作用以及它在调节T-reg谱系中关键的microRNAs中的作用有关，是这一提议的重点。创新：T细胞分化的关键调节因子调节T-reg细胞中的microRNA表达这一概念非常新颖。我们使用创新的遗传细胞谱系标记方法来测试BCL6在T-reg细胞中的作用。影响：探索BCL6作为一种新的T-reg活性调节介质可以为心肌炎和血管炎的分子病因学提供新的见解，从而促进针对BCL6的新疗法的开发，用于治疗炎症和自身免疫。) 公共卫生相关性：调节性T细胞是辅助T细胞的谱系，对于维持免疫动态平衡和抑制自身免疫性疾病不可或缺。了解这一重要T细胞亚群的表型、功能和调节，对于开发成功的治疗自身免疫病理的方法特别有必要。在这里，我们建议研究关键的转录抑制因子BCL6在调节性T细胞功能中的作用。这项工作将为调节性T细胞的分子调控提供新的见解，从而促进针对BCL6的新疗法的开发，用于治疗炎症和自身免疫。)

DESCRIPTION (provided by applicant): Regulatory T cells (T-reg cells), expressing the transcription factor FOXP3, represent a distinct lineage of helper T cells indispensable for the maintenance of immune homeostasis and inhibiting autoimmune diseases. Therefore understanding the phenotype, function and regulation of this crucial T cell subset is particularly warranted to develop successful therapeutic modalities for the treatment of autoimmune pathologies. The transcriptional repressor, BCL6, regulates several critical pathways of the immune system and acts as an oncogene in B cells. BCL6 serves as a major arbiter of T cell fates, however little is known about the role of BCL6 in T-reg cells. BCL6- deficient mice (BKO mice) develop severe inflammatory disease that resembles the disease observed in mice with known T-reg defects, although the disease is primarily limited to heart and lungs. The inflammation is spontaneous, with the majority of the mice developing the disease a few weeks following birth and the mice invariably dying at an early age. The requirement for T cells in mediating the inflammation in BKO mice suggests there is an autoimmune component to the disease. Since T-reg cells are implicated in maintaining immune homeostasis by keeping effector T cell responses from causing collateral damage and keeping inflammation in check, perturbations in T-reg function offers a likely explanation for the inflammatory disease in BKO mice. Our preliminary results demonstrate elevated levels of Th2 genes and altered microRNA profiles of BKO T-reg cells that might compromise their capacity to block the heart and lung-specific inflammation. We therefore hypothesize that BCL6 has a critical role in regulating T-reg function, particularly by stabilizing the T-reg phenotype in the context of the Th2-type inflammatory setting in vivo. How this stabilization relates to the role of BCL6 in repressing Th2 gene expression in T-reg cells and its role in regulating critical microRNAs in the T-reg lineage is the focus of this proposal. INNOVATION: The concept that a key regulator of T cell differentiation regulates microRNA expression in T-reg cells is highly novel. We use innovative genetic cell- lineage marking approaches to test the role of BCL6 in T-reg cells. IMPACT: Exploring BCL6 as a novel regulatory mediator of T-reg activity can offer new insights into the molecular etiology of myocarditis and vasculitis, thus facilitating the development of new therapies targeting BCL6 for treatment of inflammation and autoimmunity. ) PUBLIC HEALTH RELEVANCE: Regulatory T cells are lineage of helper T cells indispensable for the maintenance of immune homeostasis and inhibiting autoimmune diseases. Understanding the phenotype, function and regulation of this crucial T cell subset is particularly warranted to develop successful therapeutic modalities for the treatment of autoimmune pathologies. Here we propose to study the role of the key transcriptional repressor, BCL6, in regulatory T cell function. This work will offer new insights into the molecular regulation of regulatory T cells, thus facilitating the development of new therapies targeting BCL6 for treatment of inflammation and autoimmunity. )