Transcriptional regulation of inflammatory helper T Cell differentiation

描述（由申请人提供）：CD4+辅助性T （TH）淋巴细胞是适应性免疫反应的重要组织者，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，幼稚TH细胞进行克隆扩增和功能分化为细胞因子分泌效应细胞。效应TH细胞历来被分为TH1和TH2亚群。TH1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，TH2细胞分泌IL-4、-5和-13，它们共同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和转录激活因子（STAT）蛋白决定TH效应因子的分化，从而导致谱系特异性主转录因子的表达。最近，一种名为THIL-17、TH17或THi的新型TH亚群已成为组织炎症的关键调节因子。我们发现TH17/THJ细胞是TH1和TH2细胞的一个不同谱系，并且TH17/THi分化受IFNg和IL-4的负调控。IL-6和IL-23通过Stat3协同TH17/TH1分化。这项新的拨款旨在研究控制TH17/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TH17/ thi特异性转录和表观遗传程序。我们将首先研究STATS在TH17/THJ分化中的作用，并检验STATS是否在TH17/THJ分化过程中上调RORa和RORc。其次，我们将研究RORa在TH17/THJ分化中的作用。最后，我们将研究TH17/THJ和诱导调节性T （iTreg）细胞的分子特征。这些研究将极大地帮助我们理解控制TH17/THi分化的分子程序，并可能为TH17/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.