Role of TRIF-Dependent TLR Signaling in Intestinal Mucosa

广泛的研究表明，对肠道细菌起反应的一种侵略性粘膜T细胞亚群起作用 在炎症性肠病(IBD)的病因中起着重要作用。这些具有侵略性的T细胞被认为 作为外周血液中的免疫记忆细胞长寿，并有助于慢性和复发 疾病。证据进一步表明，一种灵活地分泌不同效应分子的T细胞， 在IBD复杂的发病机制中起着重要作用。另一个T细胞亚群是T滤泡辅助细胞(TFH)样细胞， 在动物模型中会引起严重的结肠炎，并在IBD患者的外周血中大量存在。因为 TFH样细胞是一种免疫记忆细胞，具有高度灵活的效应分子分泌，并在 肠道，它们可能在IBD的慢性炎症中起重要作用。然而，TFH样细胞的作用 在肠道炎症中的作用及其在肠道中的调节机制尚不清楚 探索过了。这项应用的目的是确定调节Tfh样细胞生成的关键途径，并 在肠道中起作用。我们已经证明了含有TIR结构域的适配器诱导的干扰素-β (TRIF)是一种通过遇到细菌和病毒而被激活的分子，在 通过T细胞的活化和功能来维持肠道内环境的稳定。我们发现TRIF 限制Tfh样细胞的产生和T细胞在肠道中分泌效应分子的灵活性 四个关键分子：IFNAR、IL27、STAT1和STAT3诱导的信号转导通路。TRIF扩增功能受损 TFH样细胞的产生和可塑性，以及TRIF水平的增加导致TFH样数的抑制 和灵活性。遗传学研究已经证实，IFNAR、IL27、STAT1和STAT3的异常 克隆氏病(CD)患者体内常发现基因。因此，通过以下三个目标，我们将 我想解释一下我们的假设，即TRIF介导的通路的损伤可以增加 功能灵活的Tfh样细胞导致CD的慢性炎症，特别是在 IL27、IFNAR、STAT1和STAT3基因的遗传变异。具体目标是：(一)。确定 TFH样细胞在肠道中维持破坏性炎症的机制。(2)。确定 TRIF调节致病TFH样细胞生成的机制。(3)。确定功能 TRIF途径中的遗传变异在致病TFH样细胞产生中的后果 在CD患者中。了解影响高侵袭性T细胞生成的靶途径可能 提出新的方法，如精准医学，在管理IBD患者亚群方面 这种炎症是由这些T细胞引起的。这个项目的结果将是对 高度侵袭性T细胞群体的基本调节机制，预计这将有一个主要的 影响我们对黏膜免疫学的理解，以及在未来许多慢性疾病的治疗中 炎症性疾病，包括IBD。

Extensive studies have shown that an aggressive mucosal T cell subset that reacts to intestinal bacteria plays an important role in the cause of inflammatory bowel disease (IBD). These aggressive T cells are thought to live long as immune-memory cells in peripheral blood and contribute to the chronicity and the relapse of the disease. Evidence further suggests that a type of T cells, which flexibly secretes different effector molecules, contributes to the complex pathogenesis of IBD. Another T cell subset, T follicular helper (Tfh)-like cells, causes severe colitis in animal models, and is abundantly found in peripheral blood of IBD patients. Because Tfh-like cells are immune-memory cells with highly flexible secretion of effector molecules and are generated in the intestine, they may contribute significantly to chronic inflammation in IBD. However, the role of Tfh-like cells in intestinal inflammation and the regulatory mechanisms of their function in the intestine have yet to be explored. The objective of this application is to identify the key pathways regulating Tfh-like cell generation and function in the intestine. We have demonstrated that TIR-domain-containing adapter-inducing interferon-β (TRIF), a molecule that is activated by encountering bacteria and viruses, plays an important role in maintaining intestinal homeostasis through direction of T cell activation and function. We have found that TRIF limits the generation of Tfh-like cells and T cell flexibility of effector molecule secretion in the intestine through the pathways induced by four key molecules; IFNAR, IL27, STAT1, and STAT3. Impairment of TRIF amplifies Tfh-like cell generation and plasticity, and increased levels of TRIF results in suppression of Tfh-like number and flexibility. Genetic studies have identified that the abnormalities in the IFNAR, IL27, STAT1, and STAT3 genes are often found in Crohn's disease (CD) patients. Therefore, through the following three aims, we would like to address our hypothesis that impairment of the TRIF-mediated pathways allows increased generation of functionally flexible Tfh-like cells that contribute to chronic inflammation in CD, particularly in patients with genetic variants in the IL27, IFNAR, STAT1, and STAT3 genes. Our specific aims are: (1). Determine the mechanism by which Tfh-like cells perpetuate destructive inflammation in the intestine. (2). Determine the mechanisms by which TRIF regulates pathogenic Tfh-like cell generation. (3). Determine the functional consequence of genetic variants within TRIF-mediated pathways in the generation of pathogenic Tfh-like cells in patients with CD. Understanding target pathways affecting the generation of highly aggressive T cells may suggest novel approaches, such as precision medicine, in the management of the subsets of IBD patients in which inflammation is caused by these T cells. The outcome of this project will be novel insight into the essential regulatory mechanisms of highly aggressive T cell populations, which is expected to have a major impact in our understanding of mucosal immunology, as well as in the future therapy of many chronic inflammatory diseases including IBD.