CD4 T cell stemness and inflammatory bowel disease

CD4 T 细胞干性与炎症性肠病

• 批准号: 10043981
• 负责人: Laurie Ellen Harrington
• 金额: $ 38.6万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-01 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10043981
• 关键词: Affect; Antigens; Autoimmune Process; CD4 Positive T Lymphocytes; Cell Surface Proteins; Cell surface; Cells; Cellular Immunity; Chronic; Chronic Disease; Clinical Trials; Colitis; Crohn' s disease; Development; Disease; Disease remission; Environment; Etiology; Exhibits; Gene Expression Profile; Human; Immune; Immune system; Inflammation; Inflammatory; Inflammatory Bowel Diseases; Intestines; Lead; Learning; Link; Maintenance; Mediating; Mus; Pathogenicity; Pathology; Patients; Phenotype; Polysaccharides; Population; Post-Translational Protein Processing; Property; Research; Role; ST6Gal I; Severity of illness; Sialic Acids; T cell differentiation; T-Lymphocyte; Testing; Ulcerative Colitis; associated symptom; chronic inflammatory disease; commensal microbes; design; exhaust; glycosyltransferase; inflammatory disease of the intestine; intestinal homeostasis; mouse model; novel; preservation; progenitor; self-renewal; sialylation; stem; stem-like cell; stemness; transcription factor

PROJECT SUMMARY/ABSTRACT Inflammatory bowel disease (IBD) is a chronic inflammatory disorder that results from a loss in intestinal homeostasis between the commensal microbiota and the immune system. Importantly, the etiology of IBD remains unknown, although numerous studies have demonstrated a central role for CD4 T cells in the induction of IBD. A tremendous amount of research has been performed to understand the functional aspects of the CD4 T cells that mediate the pathology and symptoms associated with IBD, and many of the currently approved therapies, as well as a number of treatments in clinical trials, target these properties. Still, there is not a cure for either Crohn’s Disease (CD) or Ulcerative Colitis (UC), and this may be in part because little is known regarding how pathogenic CD4 T cells perpetuate the chronicity of disease. In recent years, the importance of T cell stemness has emerged as a critical parameter that sustains protective and pathogenic cell mediated immunity. During chronic intestinal inflammation, we observe that effector CD4 T cells with stem-like properties are able to both sustain and confer disease and that these cells preferentially express ST6Gal-I-dependent α2-6 linked sialic acids on the cell surface. In addition, we find that ST6Gal-I sialylation of N-glycans is important for expression of the stemness-associated transcription factor, TCF1. These preliminary findings lead us to hypothesize that effector CD4 T cell stemness promotes and sustains chronic intestinal inflammation in both mice and humans, and that this intestinal inflammation in turn operates to preserve this unique population of T cells. Furthermore, we postulate that ST6Gal-I mediated sialylation is central to effector CD4 T cell stemness and the chronicity of disease. To test these hypotheses, we propose the following specific aims: Aim 1. Determine the impact of ST6Gal-I mediated sialylation on CD4 T cell driven intestinal inflammation and CD4 T cell stemness. Aim 2. Determine the effect of the inflammatory intestinal environment on CD4 T cell stemness. Aim 3. Determine the contribution of stem-like effector CD4 T cells to chronic intestinal inflammation. Collectively, these studies are designed to provide new information regarding how CD4 T cell stemness impacts the chronicity of IBD. Moreover, findings that result from this application will illustrate how the composition of the commensal microbiota, as well as post-translational modification of cell surface proteins, specifically N-glycan sialylation, regulates CD4 T cell pathogenicity and stemness during chronic intestinal inflammation.

项目总结/摘要 炎症性肠病（IBD）是一种慢性炎症性疾病，其由肠道炎症因子的损失引起。 体内微生物群和免疫系统之间的平衡。重要的是，IBD的病因 目前尚不清楚，尽管许多研究已经证明了CD 4 T细胞在诱导中的核心作用， IBD。已经进行了大量的研究来了解CD 4的功能方面， 介导IBD相关病理和症状的T细胞，以及许多目前批准的免疫调节剂， 治疗以及临床试验中的许多治疗以这些性质为目标。但仍然没有治愈的方法 克罗恩病（CD）或溃疡性结肠炎（UC），这可能部分是因为对 致病性CD 4 T细胞如何使疾病长期存在。近年来，T细胞的重要性 干性已经成为维持保护性和致病性细胞介导的免疫的关键参数。 在慢性肠道炎症期间，我们观察到具有干细胞样特性的效应CD 4 T细胞能够 这些细胞优先表达ST 6 Gal-I依赖性α2-6连接的唾液酸， 细胞表面的酸性物质。此外，我们发现N-聚糖的ST 6 Gal-I唾液酸化对于表达 干细胞相关转录因子TCF 1这些初步发现使我们假设， 效应CD 4 T细胞干细胞促进和维持小鼠和小鼠的慢性肠道炎症， 这种肠道炎症反过来又保护了这种独特的T细胞群， 细胞此外，我们推测ST 6 Gal-I介导的唾液酸化是效应CD 4 T细胞的中心， 以及疾病的慢性化。为了检验这些假设，我们提出了以下具体目标： 目标1。确定ST 6 Gal-I介导的唾液酸化对CD 4 T细胞驱动的肠道炎症的影响 和CD 4 T细胞干细胞。 目标二。确定炎症性肠道环境对CD 4 T细胞干细胞的影响。 目标3.确定干细胞样效应CD 4 T细胞对慢性肠道炎症的贡献。 总的来说，这些研究旨在提供关于CD 4 T细胞干细胞性 影响IBD的慢性化。此外，这项应用的结果将说明 肠道微生物群的组成，以及细胞表面蛋白的翻译后修饰， 特别是N-聚糖唾液酸化，调节慢性肠道疾病中CD 4 T细胞的致病性和干性。 炎症