Transcriptional regulation of inflammatory helper T Cell differentiation

描述（由申请人提供）：CD 4+辅助性T（TH）淋巴细胞是适应性免疫应答的重要组织者，也是免疫介导的自身免疫性和过敏性疾病的关键介质。在被抗原呈递细胞（ARC）激活后，初始TH细胞经历克隆扩增和功能分化成分泌精氨酸的效应细胞。效应TH细胞历来被分为TH 1和TH 2亚群。TH 1细胞产生干扰素g（IFNg）并调节抗原呈递和细胞免疫。另一方面，TH 2细胞分泌IL-4、IL-5和IL-13，它们一起调节体液免疫和抗寄生虫免疫。TH激活过程中的细胞因子微环境通过选择性信号转导子和转录激活子（STAT）蛋白导致谱系特异性主转录因子的表达来决定TH效应子分化。最近，一种新的TH亚群，命名为蒂尔-17，TH 17或THi，使IL-17已成为组织炎症的关键调节因子。我们发现TH 17/THJ细胞是与TH 1和TH 2细胞不同的TH细胞谱系，并且TH 17/THi分化受IFNg和IL-4负调控。IL-6和IL-23通过Stat 3在TH 17/TH 1分化中协同作用。这项新的资助旨在研究控制TH 17/THi分化的分子程序。我们的中心假设是细胞因子介导的STATS激活启动TH 17/THi特异性转录和表观遗传程序。我们将首先研究STATS在TH 17/THi分化中的功能，并测试STATS在TH 17/THJ分化期间是否具有上调RORa和RORc的功能。其次，我们将研究RORa在TH 17/THJ分化中的功能。最后，我们将研究TH 17/THJ和诱导型调节性T（iTreg）细胞的分子特化。这些研究将极大地有利于我们对TH 17/THi分化的分子程序的理解，并可能为TH 17/THi介导的免疫疾病提供新的治疗方法。

DESCRIPTION (provided by applicant): CD4+ helper T (TH) lymphocytes are essential organizers of adaptive immune responses and key mediators in immune-mediated autoimmune and allergic diseases. Upon activation by the antigen-presenting cells (ARC), naive TH cells undergo clonal expansion and functional differentiation into cytokine-secreting effector cells. Effector TH cells have been historically classified into TH1 and TH2 subsets. TH1 cells make interferon g (IFNg) and regulate antigen presentation and cellular immunity. TH2 cells, on the other hand, secrete IL-4, -5 and -13, which together regulate humoral and anti-parasite immunity. The cytokine microenvironment during TH activation determines TH effector differentiation, through selective signal transducer and activator of transcription (STAT) proteins leading to expression of lineage-specific master transcription factors. Recently, a novel TH subset, named THIL-17, TH17 or THi, that make IL-17 has emerged as critical regulators of tissue inflammation. We found that TH17/THJ cells are a distinct lineage of TH cells from TH1 and TH2 cells and TH17/THi differentiation is negatively regulated by IFNg and IL-4. IL-6 and IL-23 synergize in TH17/TH1 differentiation through Stat3. This new grant aims at investigating the molecular programs governing TH17/THi differentiation. Our central hypothesis is that cytokine mediated STATS activation initiates TH17/THi-specific transcriptional and epigenetic programs. We will first investigate the function of STATS in TH17/THi differentiation and test if STATS functions to upregulate RORa and RORc during TH17/THJ differentiation. Secondly, we will investigate the function of RORa in TH17/THJ differentiation. Lastly, we will Investigate the molecular specification of TH17/THJ and inducible regulatory T (iTreg) cells. These studies will greatly benefit our understanding of the molecular programs governing TH17/THi differentiation and may suggest novel treatments of TH17/THi-mediated immune diseases.