Role of MAIT cells in a mouse model of spontaneous colitis

项目摘要。炎症性肠病（IBD）是慢性的，并且引起显著的发病率。一个 据估计，美国目前有300万成年人患有IBD，并且没有治愈方法。很明显， 它受到宿主遗传学、微生物群和免疫系统的影响。因此进一步 理解这些因素之间的相互作用对于开发新的免疫疗法至关重要。先前 IBD的小鼠模型对于研究人类疾病是有限的，需要人工诱导IBD， 易感小鼠新的自发性结肠炎模型是必要的，以剖析新的免疫调节剂的作用。 参与者及其调节疾病和作为治疗靶点的能力。粘膜相关不变T MAIT（MAIT）细胞是一类新的先天性T淋巴细胞，在人类血液和粘膜中高度丰富。 组织包括肠道它们可被细菌衍生的代谢物有效激活， 进化保守的主要组织相容性复合体I类相关分子，MR 1。迄今为止， 与一系列炎症性疾病有关然而，它们在IBD中的作用和可能的相关性 他们的参与和疾病的过程之间仍然不确定。IBD患者表现出 MAIT细胞显著浸润到发炎的肠组织中，并显示出炎症特征。我们有 鉴定了一种新的近交系小鼠品系，其在初级免疫器官和外周血中具有大量MAIT细胞 组织，包括结肠，与迄今为止分析的其他小鼠品系相比。这些老鼠自发地 发展出模仿人类疾病的结肠炎的病理特征。我们建议检验这个假设， 这些小鼠中MAIT细胞数量的增加影响它们对结肠炎的易感性。本项目的目标 是建立MAIT细胞，微生物群和遗传学如何导致发展的相互作用， 自发性结肠炎在Aim 1中，我们将评估MAIT细胞积累、激活和基因表达的动态变化。 这一新小鼠品系的肠道白细胞的表达谱作为年龄的函数。在目标2中，我们 检查MAIT细胞和/或微生物群对结肠炎发展的贡献， 新的老鼠品种这些研究将为理解MAIT的潜在作用开辟新的可能性 结肠炎中的细胞，以便它可以用于治疗用途，以改善人类健康。

Project Summary. Inflammatory bowel diseases (IBD) are chronic and cause significant morbidity. An estimated 3 million adults in the USA currently live with IBD and no cure is available. It is clear that the disease is complex with influences from host genetics, microbiota and the immune system. Therefore, further understanding of the interplay between these factors is crucial to developing novel immunotherapies. Previous mouse models of IBD are limited for studying human disease, entailing the artificial induction of IBD in susceptible mice. Newer models of spontaneous colitis are necessary to dissect the roles of novel immune players and their ability to modulate disease and serve as therapeutic targets. Mucosal-associated invariant T (MAIT) cells are a novel class of innate-like T lymphocytes, highly abundant in human blood and in mucosal tissues, including the gut. They are potently activated by bacterial-derived metabolites presented by the evolutionary conserved major histocompatibility complex class I-related molecule, MR1. To date, they have been implicated in a range of inflammatory diseases. However, their role in IBD and the possible correlations between their involvement and the course of the disease remains uncertain. Patients with IBD demonstrate significant infiltration of MAIT cells into inflamed gut tissue and display an inflammatory profile. We have identified a new inbred mouse strain with high numbers of MAIT cells in primary immune organs and peripheral tissues, including the colon, compared to other mouse strains analyzed to date. These mice spontaneously develops pathologic features of colitis that emulate the human disease. We propose to test the hypothesis that increased MAIT cell numbers in these mice affects their susceptibility to colitis. The objectives of this project are to establish the interplay of how MAIT cells, microbiota and genetics lead to the development of spontaneous colitis. In Aim1, we will assess the dynamics of MAIT cell accumulation, activation and gene expression profile of the gut leukocytes of this new mouse strain as a function of age. In Aim 2, we will examine the contributions that MAIT cells and/or the microbiota both have towards the development of colitis in this new mouse strain. These studies will open up new possibilities for understanding the potential role of MAIT cells in colitis so that it can be exploited for therapeutic usage to improve human health.