Transcriptional regulation of inflammatory helper T Cell differentiation

描述(由申请人提供)：CD4+辅助T(TH)淋巴细胞是适应性免疫反应的基本组织者，也是免疫介导性自身免疫和变态反应性疾病的关键介质。在抗原提呈细胞(ARC)的激活下，幼稚TH细胞经过克隆性扩增和功能分化为分泌细胞因子的效应细胞。效应器TH细胞历来被分为TH1和TH2亚群。Th1细胞产生干扰素g(IFNG)，调节抗原提呈和细胞免疫。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)蛋白导致谱系特异性主转录因子的表达，决定TH效应因子的分化。最近，一个新的TH亚群，命名为Thil-17，TH17或Thi，它产生了IL-17，成为组织炎症的关键调节因子。我们发现TH17/THJ细胞是不同于TH1和TH2细胞的TH细胞谱系，并且TH17/THI细胞的分化受IFNG和IL-4的负调控。IL-6和IL-23通过STAT3在TH17/TH1分化中起协同作用。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激活启动了TH17/THI特异的转录和表观遗传程序。我们将首先研究STATS在TH17/THI分化中的作用，并检测STATS在TH17/THJ分化过程中是否上调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和诱导型调节性T细胞(ITreg)的分子特性。这些研究将极大地帮助我们理解调控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.