control of Inflammation by regulatory T cells and BCL6

描述（由申请人提供）：表达转录因子FOXP 3的调节性T细胞（T-reg细胞）代表了维持免疫稳态和抑制自身免疫性疾病所必需的辅助性T细胞的独特谱系。因此，了解这一关键T细胞亚群的表型、功能和调节对于开发用于治疗自身免疫性病理的成功治疗模式是特别必要的。转录抑制因子BCL 6调节免疫系统的几个关键途径，并在B细胞中作为致癌基因发挥作用。BCL 6是T细胞命运的主要仲裁者，但对BCL 6在T-reg细胞中的作用知之甚少。BCL 6缺陷小鼠（BKO小鼠）发生严重的炎症性疾病，类似于在已知T-reg缺陷的小鼠中观察到的疾病，尽管该疾病主要限于心脏和肺。这种炎症是自发的，大多数小鼠在出生后几周内就会患上这种疾病，并且小鼠总是在早期死亡。在BKO小鼠中介导炎症对T细胞的需求表明该疾病存在自身免疫成分。由于T-reg细胞通过保持效应T细胞应答不引起附带损伤和保持炎症来维持免疫稳态，因此T-reg功能的扰动为BKO小鼠中的炎性疾病提供了可能的解释。我们的初步结果表明，Th 2基因水平升高，BKO T-reg细胞的microRNA谱改变，这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BCL 6在调节T-reg功能中具有关键作用，特别是通过在体内Th 2型炎症环境中稳定T-reg表型。这种稳定性如何与BCL 6在抑制T-reg细胞中Th 2基因表达中的作用及其在调节T-reg谱系中关键microRNA中的作用相关是本提案的重点。创新：T细胞分化的关键调节因子调节T-reg细胞中microRNA表达的概念非常新颖。我们使用创新的遗传细胞谱系标记方法来测试BCL 6在T-reg细胞中的作用。影响：探索BCL 6作为T-reg活性的新型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BCL 6治疗炎症和自身免疫的新疗法的开发。) 公共卫生相关性：调节性T细胞是维持免疫稳态和抑制自身免疫性疾病所必需的辅助性T细胞谱系。了解这一关键T细胞亚群的表型、功能和调节对于开发用于治疗自身免疫性病理的成功治疗模式是特别必要的。在这里，我们建议研究的关键转录抑制因子，BCL 6，在调节T细胞功能的作用。这项工作将为调节性T细胞的分子调节提供新的见解，从而促进靶向BCL 6治疗炎症和自身免疫的新疗法的开发。)

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. )