Regulation of effector CD4 T cell subsets during inflammatory bowel disease

描述(申请人提供)：十多年来，炎症性肠病(IBD)和包括多发性硬化症和类风湿性关节炎在内的其他慢性炎症性疾病一直被描述为Th1介导的疾病，因为产生IFN3的CD4T细胞在疾病患者中普遍存在，并且IFN3强烈激活巨噬细胞，加剧炎症。然而，大量自身免疫性/慢性炎症性疾病动物模型的最新数据表明，一种新的效应CD4T细胞谱系--产生IL-17的Th17细胞--负责疾病的诱导。有趣的是，这些慢性炎症性疾病的发病与炎症部位的IFN3和IL-17效应CD4T细胞的数量增加有关，从而开启了关于这些效应CD4T细胞在疾病中的个体作用的辩论。事实上，Th1CD4T细胞对IBD发生发展的影响仍存在争议。在某些结肠炎模型中，IFN3似乎不是诱导疾病所必需的，但已经证明，体外极化的Th1细胞的转移可以诱发小鼠的实验性结肠炎。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效应分子CD4T细胞在介导慢性炎症中可能发挥了独立于IFN3分泌的未知角色，因为这些转录因子不是产生IL-17所必需的。我们假设Th1CD4T细胞以一种Tbet依赖、STAT4依赖和非IFN3依赖的机制诱导IL-23依赖的结肠炎。我们提出以下具体目标来验证这一假说：目的1.确定体内来源的IFN3 CD4T细胞在IL-23依赖型结肠炎中的作用。目的2.确定IBD时CD4T细胞亚群中Tbet产生的先决条件。目的3.确定结肠炎时CD4T细胞对STAT4信号的需求。总而言之，这些研究旨在提供有关结肠炎细胞介质的新信息，并准确定义控制致病CD4T细胞发育的属性和分子调节因素。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。 公共卫生相关性：炎症性肠病是CD4T细胞反应失调的结果，目前还不完全清楚CD4T细胞是如何致病的。通过研究CD4T细胞引起结肠炎的起源和破译它们致病的机制，我们将获得新的信息，这些信息可能有助于开发可能的治疗方法来减轻炎症性肠病。

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.