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IFN3的CD4 T细胞在患病患者中普遍存在，IFN3强烈激活巨噬细胞，增强炎症。然而，最近来自许多自身免疫性/慢性炎症性疾病动物模型的数据表明，一种新的效应CD4 T细胞谱系，即产生il -17的Th17细胞，负责诱导疾病。有趣的是，这些慢性炎症性疾病的发病与炎症部位IFN3+和IL-17+效应CD4 T细胞数量的升高有关，这开启了关于这些效应CD4 T细胞群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Th1细胞的转移可以引起小鼠实验性结肠炎。重要的是，Th1相关的转录因子Tbet和STAT4是诱导实验性IBD所必需的，这表明Th1效应CD4 T细胞在介导慢性炎症中独立于IFN3分泌的可能未被认识到的作用，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细胞以一种依赖于tbet、stat4和非ifn3的机制诱导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。确定体内源性IFN3+ CD4 T细胞在il -23依赖性结肠炎中的作用。目标2。确定IBD期间CD4 T细胞室Tbet的先决条件。目标3。确定结肠炎期间CD4 T细胞对STAT4信号的需求。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。这些发现有可能为消除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. PUBLIC HEALTH RELEVANCE: Inflammatory bowel disease is the result of dysregulated CD4 T cell responses and it is not fully understood what CD4 T cells do to cause disease. By investigating the origin of the colitis-inducing of CD4 T cells and decipher the mechanisms by which they cause disease, we will learn novel information that may be beneficial for the development of possible therapies to alleviate inflammatory bowel diseases.