Regulation of effector CD4 T cell subsets during inflammatory bowel disease

炎症性肠病期间效应 CD4 T 细胞亚群的调节

• 批准号: 8638951
• 负责人: Laurie Ellen Harrington
• 金额: $ 30.09万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-04-01 至 2015-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8638951
• 关键词: Address; Animal Model; Autoimmune Process; Biochemical; CD4 Positive T Lymphocytes; Cell physiology; Cells; Chronic; Colitis; Data; Dependence; Development; Disease; Generations; Goals; Heterogeneity; In Vitro; Individual; Inflammation; Inflammatory; Inflammatory Bowel Diseases; Interferons; Interleukin-17; Learning; Mediating; Mediator of activation protein; Modeling; Molecular; Multiple Sclerosis; Mus; Patients; Population; Process; Production; Property; Regulation; Reporter; Research Design; Rheumatoid Arthritis; Role; STAT4 gene; Series; Signal Transduction; Signaling Molecule; Site; T cell response; T-Lymphocyte; T-Lymphocyte Subsets; Testing; Th1 Cells; cytokine; design; in vivo; interleukin-23; macrophage; new therapeutic target; novel; public health relevance; transcription factor

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.

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Th 1介导的疾病，因为产生IFN 3的CD 4 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CD 4 T细胞的新谱系，即产生IL-17的Th 17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IFN 3+和IL-17+效应CD 4 T细胞的数量增加有关，从而引发了关于这些效应CD 4 T细胞群体在疾病期间的个体作用的争论。事实上，Th 1 CD 4 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，IFN 3似乎不是疾病诱导所必需的，但已经证明体外极化的Th 1细胞的转移可以在小鼠中引起实验性结肠炎。重要的是，Th 1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Th 1效应CD 4 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Th 1 CD 4 T细胞的功能是以Tbet依赖性、STAT 4依赖性和非IFN 3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 + CD 4 T细胞在IL-23依赖性结肠炎中的作用。 目标2.确定IBD期间CD 4 T细胞区室中Tbet的先决条件。 目标3.确定结肠炎期间CD 4 T细胞中STAT 4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CD 4 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。

项目成果

Astrocytes modulate the polarization of CD4+ T cells to Th1 cells.

• DOI: 10.1371/journal.pone.0086257
• 发表时间: 2014
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Beurel E;Harrington LE;Buchser W;Lemmon V;Jope RS
• 通讯作者: Jope RS

Inflammatory T helper 17 cells promote depression-like behavior in mice.

• DOI: 10.1016/j.biopsych.2012.09.021
• 发表时间: 2013-04-01
• 期刊: BIOLOGICAL PSYCHIATRY
• 影响因子: 10.6
• 作者: Beurel, Eleonore;Harrington, Laurie E.;Jope, Richard S.
• 通讯作者: Jope, Richard S.

Regulation of Th1 cells and experimental autoimmune encephalomyelitis by glycogen synthase kinase-3.

通过糖原合酶激酶3的TH1细胞和实验自身免疫性脑脊髓炎的调节。

• DOI: 10.4049/jimmunol.1203057
• 发表时间: 2013-05-15
• 期刊: Journal of immunology (Baltimore, Md. : 1950)
• 作者: Beurel E;Kaidanovich-Beilin O;Yeh WI;Song L;Palomo V;Michalek SM;Woodgett JR;Harrington LE;Eldar-Finkelman H;Martinez A;Jope RS
• 通讯作者: Jope RS