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）一直被描述为 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，并且 IFN3 会强烈激活巨噬细胞，从而加剧炎症。然而，来自多种自身免疫/慢性炎症性疾病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，这些慢性炎症性疾病的发作与炎症部位的 IFN3 和 IL-17 效应 CD4 T 细胞数量增加有关，这引发了关于这些效应 CD4 T 细胞群在疾病期间各自作用的争论。事实上，Th1 CD4 T细胞对IBD发展的影响仍存在争议。在某些结肠炎模型中，IFN3似乎并不是疾病诱导所必需的，但已证明体外极化的Th1细胞的转移可以在小鼠中引发实验性结肠炎。重要的是，Th1 相关转录因子 Tbet 和 STAT4 是诱导实验性 IBD 所必需的，这表明 Th1 效应 CD4 T 细胞在介导独立于 IFN3 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. 确定体内衍生的 IFN3 CD4 T 细胞在 IL-23 依赖性结肠炎期间的作用。 目标 2. 确定 IBD 期间 CD4 T 细胞室中 Tbet 的先决条件。 目标 3. 确定结肠炎期间 CD4 T 细胞对 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除炎症性肠病的治疗和预防策略确定新的靶标。

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.