Regulation of effector CD4 T cell subsets during inflammatory bowel disease

描述（由申请人提供）：十多年来，炎症性肠病（IBD）和其他慢性炎症性疾病（包括多发性硬化症和类风湿性关节炎）被描述为Th1介导的疾病，因为产生IFN 3的CD4 T细胞在患病患者中普遍存在，IFN 3强烈激活巨噬细胞，增强炎症。然而，来自许多自身免疫性/慢性炎症性疾病的动物模型的最新数据表明，效应CD4 T细胞的新谱系，即产生IL-17的Th17细胞，负责诱导疾病。有趣的是，这些慢性炎性疾病的发作与炎症部位IFN3+和IL-17+效应CD4 T细胞的数量增加有关，从而引发了关于这些效应CD4 T细胞群体在疾病期间的个体作用的争论。事实上，Th1 CD4 T细胞对IBD发展的影响仍然存在争议。在某些结肠炎模型中，IFN3似乎不是疾病诱导所必需的，但已经证明体外极化的Th1细胞的转移可以在小鼠中引起实验性结肠炎。重要的是，Th1相关的转录因子Tbet和STAT 4是诱导实验性IBD所必需的，这表明Th1效应CD4 T细胞在介导不依赖于IFN 3分泌的慢性炎症中可能具有未被认识到的作用，因为这些转录因子不是IL-17产生所必需的。我们假设Th1 CD4 T细胞的功能是以Tbet依赖性、STAT4依赖性和非IFN3依赖性机制诱导IL-23依赖性结肠炎。我们提出以下具体目标来检验这一假设：目标1。确定体内来源的IFN 3 + CD4 T细胞在IL-23依赖性结肠炎中的作用。 目标二。确定IBD期间CD4 T细胞区室中Tbet的先决条件。 目标3。确定结肠炎期间CD4 T细胞中STAT4信号传导的需求。总的来说，这些研究旨在提供有关结肠炎细胞介质的新信息，并精确定义控制致病性CD4 T细胞发育的特性和分子调节因子。这些发现有可能为旨在消融炎症性肠病的治疗和预防策略确定新的靶点。

DESCRIPTION (provided by applicant): For over a decade, inflammatory bowel disease (IBD) and other chronic inflammatory disorders including multiple sclerosis and rheumatoid arthritis have been described as Th1-mediated disorders because IFN3- producing CD4 T cells are prevalent in diseased patients and IFN3 strongly activates macrophages, potentiating inflammation. However recent data from animal models of numerous autoimmune/chronic inflammatory disorders suggests that a new lineage of effector CD4 T cells, the IL-17-producing Th17 cells, are responsible for the induction of disease. Interestingly, the onset of these chronic inflammatory diseases is associated with elevated numbers of both IFN3+ and IL-17+ effector CD4 T cells at the sites of inflammation, opening the debate on the individual roles of these effector CD4 T cell populations during disease. In fact, the impact of Th1 CD4 T cells on the development of IBD remains controversial. In certain models of colitis, IFN3 does not appear necessary for disease induction, yet it has been demonstrated that transfer of in vitro- polarized Th1 cells can elicit experimental colitis in mice. Importantly, Th1-associated transcription factors Tbet and STAT4 are required to induce experimental IBD, suggesting a possibly unrecognized role for Th1 effector CD4 T cells in mediating chronic inflammation independent of IFN3 secretion, as these transcription factors are not required for IL-17 production. We hypothesize that Th1 CD4 T cells function to induce IL- 23-dependent colitis in a Tbet-dependent, STAT4-dependent, and non-IFN3-dependent mechanism. We propose the following specific aims to test this hypothesis: Aim 1. To determine the role of in vivo derived IFN3+ CD4 T cells during IL-23-dependent colitis. Aim 2. To determine the prerequisite for Tbet in the CD4 T cell compartment during IBD. Aim 3. To determine the requirement for STAT4 signaling in CD4 T cells during colitis. Collectively these studies are designed to provide new information regarding the cellular mediators of colitis and to precisely define the properties and molecular regulators which control the development of pathogenic CD4 T cells. These findings have the potential to identify new targets for therapeutic and preventative strategies designed to ablate inflammatory bowel disease.