Modulation of in vivo MAIT cell responses with diverse MR1 ligands

项目摘要 肺部疾病是一个主要的健康问题，肺炎是#年死亡的主要感染性原因。 年幼的孩子。早期的呼吸道感染与哮喘的易感性增加有关； 每年困扰2.5亿多人的炎症性疾病，患病率有所上升 在过去的十年里。然而，由于缺乏针对许多引起肺炎的病原体和 抗生素抗药性细菌的出现需要其他方法。粘膜相关不变量T (MAIT)细胞构成了人肺内大量的效应者群体，高达肺T细胞的9% 健康个体的细胞。MAIT细胞识别合成核黄素(维生素B2)的微生物衍生物 由MHC-I类相关分子(MR1)提出。由于这种生物合成的广泛保守性 在细菌和真菌之间，MAIT细胞促进对广泛的呼吸道病原体的免疫。麦芽 细胞在预防哮喘和减少呼吸道炎症方面也有牵连。然而，除了 在介绍维生素合成的衍生物时，最近的研究表明，MR1也可以结合药物和 药物代谢物可以是MAIT细胞的激动剂或非激动剂，这表明药物可能会阻碍 MR1介导的内源微生物代谢物的呈递，这可能对 易患肺炎或哮喘。而核黄素合成的衍生物增加了MAIT细胞的丰度 和细胞因子的产生，这些分子的不稳定导致在生理条件下的快速降解 条件，限制了它们的治疗潜力。我们将对MR1结合药物的方式进行首次评估 对MAIT细胞发育的影响以及非维生素如何获得MR1配体的首次体内评估 影响MAIT细胞对生理相关肺部疾病的反应。我们也将表演最多的 迄今为止，用于新型MAIT细胞激动剂的广泛虚拟屏幕使用反应性对接来模拟 一个带有MR1的K43的Schiff碱--这是已知的最强MAIT细胞激动剂的关键特征 MR1折叠为表面表达。在体外验证了MR1结合和MAIT细胞的激动活性之后， 这些新型激动剂的免疫调节作用将在体内得到证实。我们假设我们会 鉴定新的MAIT细胞激动剂，在给予非激动型MR1的同时增强肺免疫功能 结合药物可在体内抑制MAIT细胞的发育和功能。

Project Summary Pulmonary diseases are a major health concern, with pneumonia the leading infectious cause of mortality for young children. Respiratory infections in early life are associated with increased susceptibility to asthma; an inflammatory disorder that afflicts more than 250 million people each year and has increased in prevalence during the past decade. However, the lack of vaccines for many of the pathogens that cause pneumonia and the emergence of antibiotic resistant bacteria necessitate alternative approaches. Mucosal-associated invariant T (MAIT) cells comprise a substantial effector population within human lungs, reaching up to 9% of pulmonary T cells in healthy individuals. MAIT cells recognize microbial derivatives of riboflavin (vitamin B2) synthesis presented by the MHC class-I related (MR1) molecule. Due to the broad conservation of this biosynthetic pathway among bacteria and fungi, MAIT cells promote immunity to a wide array of respiratory pathogens. MAIT cells have also been implicated in preventing asthma and reducing airway inflammation. However, in addition to presenting derivatives of vitamin synthesis, recent work has demonstrated that MR1 can also bind drugs and drug metabolites that can either be agonists or non-agonists of MAIT cells, suggesting that drugs may hinder MR1-mediated presentation of endogenous microbial metabolites, which could have implications for the susceptibility to pneumonia or asthma. While derivatives of riboflavin synthesis increase MAIT cell abundance and cytokine production in vivo, the instability of these molecules results in rapid degradation under physiological conditions, limiting their therapeutic potential. We will perform the first evaluation of how MR1 binding drugs impact the development of MAIT cells and the first in vivo assessment of how non-vitamin derived MR1 ligands affect MAIT cell responses to physiologically relevant pulmonary conditions. We will also perform the most extensive virtual screen to date for novel MAIT cell agonists using Reactive Docking to simulate the formation of a Schiff base with K43 of MR1 – a key characteristic of the strongest known MAIT cell agonists the promotes MR1 folding for surface expression. Following validation of MR1 binding and MAIT cell agonistic activity in vitro, the immunomodulatory effects of these novel agonists will be established in vivo. We hypothesize that we will identify novel MAIT cell agonists that enhance pulmonary immunity, while administration of non-agonistic MR1 binding drugs can inhibit the development and function of MAIT cells in vivo.