Function and regulation of mucosal associated invariant T cells in the lung

项目概要/摘要 哮喘仍然是一个严重的公共卫生威胁，治疗需求未得到满足。的 成功疗法的开发依赖于对免疫的更深入了解 涉及的子集和途径。 MAIT 细胞是识别微生物的先天性 T 细胞 核黄素代谢物由 MR1 呈现，可以通过 TCR 依赖性和 独立的途径。有趣的是，之前的研究表明，两者之间存在负相关关系。 MAIT 细胞和人类哮喘。 MAIT 细胞在哮喘发生和发展中的精确作用 然而，恶化情况仍然未知。我们假设 MAIT 细胞的缺陷 哮喘患者会加剧气道对过敏原的炎症反应 其他刺激，增加 MAIT 细胞数量可能有助于预防哮喘发展 和加剧。使用已故器官捐献者的新鲜肺部样本，我们将检查 严重哮喘患者肺驻留 MAIT 细胞的丰度、异质性和功能 并控制没有肺部疾病的个体。我们将使用 MAIT 细胞缺陷小鼠和收养小鼠 转移策略来探究 MAIT 细胞在过敏原和空气污染物中的具体作用 诱发气道炎症。最后，我们将测试是否可以通过以下方式增加 MAIT 细胞的数量： 工程益生菌菌株可以帮助预防严重哮喘的发展和恶化。

Project Summary/Abstract Asthma remains a serious public health threat with unmet therapeutic needs. The development of successful therapies relies a more in-depth understanding of the immune subsets and pathways involved. MAIT cells are innate-like T cells that recognize microbial riboflavin metabolites presented by MR1 and can function through both TCR dependent and independent pathways. Interestingly, previous studies indicated an inverse association between MAIT cells and human asthma. The precise role of MAIT cells in asthma development and exacerbation, however, remains unknown. We hypothesize that a deficiency of MAIT cells in asthma patients contributes to exacerbated airway inflammatory responses to allergen and other stimulus, and that increasing MAIT cell numbers may help prevent asthma development and exacerbation. Using fresh lung samples from deceased organ donors, we will examine the abundance, heterogeneity and function of lung-resident MAIT cells in severe asthma patients and control individuals without lung diseases. We will use MAIT cell deficient mice and adoptive transfer strategies to interrogate the specific roles of MAIT cells in allergen and air pollutant- induced airway inflammation. Finally, we will test whether boosting the number of MAIT cells by an engineered probiotic strain can help prevent severe asthma development and exacerbation.