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，肺炎是主要的传染性死亡原因， 年幼的孩子。生命早期的呼吸道感染与哮喘易感性增加有关; 每年折磨超过2.5亿人的炎症性疾病， 在过去的十年里。然而，由于缺乏针对许多导致肺炎的病原体的疫苗， 抗生素抗性细菌的出现需要替代方法。粘膜相关不变T （MAIT）细胞在人肺内包含大量效应细胞群，达到肺T细胞的9%。 健康人的细胞。MAIT细胞识别核黄素（维生素B2）合成的微生物衍生物 由MHC I类相关（MR 1）分子呈递。由于这种生物合成的广泛保护， 作为细菌和真菌之间的免疫途径，MAIT细胞促进对各种呼吸道病原体的免疫。MAIT 细胞还涉及预防哮喘和减少气道炎症。不过除了 最近的研究表明，MR 1也可以结合药物， 药物代谢产物可以是MAIT细胞的激动剂或非激动剂，这表明药物可能阻碍MAIT细胞的增殖。 MR 1介导的内源性微生物代谢产物的呈递，这可能对 易患肺炎或哮喘。而核黄素合成的衍生物增加MAIT细胞丰度 和细胞因子的产生，这些分子的不稳定性导致在生理条件下快速降解， 条件，限制其治疗潜力。我们将进行第一次评估如何MR 1结合药物 影响MAIT细胞的发育，并首次在体内评估非维生素衍生的MR 1配体 影响MAIT细胞对生理相关肺部疾病的反应。我们也将表演最 迄今为止，使用反应性对接来模拟MAIT细胞激动剂的形成， 具有MR 1的K43的席夫碱-促进的最强已知MAIT细胞激动剂的关键特征 用于表面表达的MR 1折叠。在体外验证MR 1结合和MAIT细胞激动活性后， 这些新激动剂的免疫调节作用将在体内建立。我们假设我们会 鉴定增强肺免疫新的MAIT细胞激动剂，同时施用非激动性MR 1 结合药物可以抑制MAIT细胞在体内的发育和功能。

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.