CD4 T cell stemness and inflammatory bowel disease

项目摘要/摘要 炎症性肠病(IBD)是一种慢性炎症性疾病，由肠道丢失引起。 共生微生物区系和免疫系统之间的动态平衡。重要的是，IBD的病因学 目前尚不清楚，尽管许多研究表明CD4T细胞在诱导过程中起着中心作用 IBD的症状。人们已经进行了大量的研究，以了解CD4的功能方面 介导与IBD相关的病理和症状的T细胞，以及目前批准的许多 治疗方法以及临床试验中的一些治疗方法都针对这些特性。尽管如此，还是没有治愈的办法 克罗恩病(CD)或溃疡性结肠炎(UC)，这可能部分是因为人们对 致病的CD4T细胞如何使疾病的慢性化永久化。近年来，T细胞的重要性 干细胞特性已成为维持保护性和致病性细胞免疫的关键参数。 在慢性肠炎期间，我们观察到具有干细胞样特性的效应器CD4T细胞能够 这些细胞优先表达ST6Gal-I依赖的α2-6连接唾液酸 细胞表面的酸性物质。此外，我们还发现N-糖链的ST6Gal-I唾液酸化对其表达具有重要意义。 与茎相关的转录因子TCF1。这些初步的发现使我们假设 效应分子CD4T细胞的干细胞特性促进和维持小鼠和 这种肠道炎症反过来又能保护这一独特的T细胞种群 细胞。此外，我们推测ST6Gal-I介导的唾液酸化是效应CD4T细胞的中心 茎和疾病的慢性性。为了检验这些假设，我们提出了以下具体目标： 目的1.确定ST6Gal-I介导的唾液酸化对CD4T细胞驱动的肠炎症的影响 和CD4T细胞干细胞性。 目的2.探讨炎性肠道环境对CD4T细胞干细胞分化的影响。 目的3.探讨干细胞样效应细胞CD4T细胞在慢性肠炎中的作用。 总的来说，这些研究旨在提供有关CD4T细胞干性的新信息 影响IBD的慢性化。此外，这项申请的结果将说明 共生微生物区系的组成，以及细胞表面蛋白的翻译后修饰， 具体地说，N-葡聚糖唾液酸化调节慢性肠道中CD4T细胞的致病性和干性 发炎。

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.