control of Inflammation by regulatory T cells and BCL6

描述（由申请人提供）：表达转录因子FOXP3的调节性T细胞（T-reg细胞）是一种独特的辅助性T细胞，在维持免疫稳态和抑制自身免疫性疾病中不可或缺。因此，了解这一关键T细胞亚群的表型、功能和调控，对于开发出治疗自身免疫性疾病的成功治疗模式尤为必要。转录抑制因子BCL6调节免疫系统的几个关键途径，并在B细胞中充当致癌基因。BCL6是T细胞命运的主要仲裁者，然而，人们对BCL6在T- regg细胞中的作用知之甚少。BCL6-缺陷小鼠（BKO小鼠）发展为严重的炎症性疾病，类似于已知T-reg缺陷小鼠所观察到的疾病，尽管这种疾病主要局限于心脏和肺部。这种炎症是自发的，大多数老鼠在出生后几周就患上了这种疾病，而且老鼠总是在很小的时候死亡。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细胞通过防止效应T细胞反应引起附带损伤和控制炎症来维持免疫稳态，因此T-reg功能的紊乱可能是BKO小鼠炎症性疾病的一种解释。我们的初步结果表明，BKO T-reg细胞的Th2基因水平升高和microRNA谱的改变可能会损害它们阻断心脏和肺部特异性炎症的能力。因此，我们假设BCL6在调节T-reg功能方面具有关键作用，特别是在体内th2型炎症环境下稳定T-reg表型。这种稳定性与BCL6在T-reg细胞中抑制Th2基因表达的作用及其在T-reg谱系中调节关键microrna的作用之间的关系是本研究的重点。创新：T细胞分化的关键调节因子调节T-reg细胞中microRNA表达的概念是非常新颖的。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提供新的见解，从而促进针对BCL6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. )