Lung Resident, MR1-Restricted T Cells: Association with Differential Outcomes Following Exposure to M. Tuberculosis

项目摘要 在人类中，气溶胶暴露于结核分枝杆菌（Mtb）的结果是不同的结果， 范围从无感染和/或清除到进行性疾病。肺部的免疫效应物 一个关键的作用是决定暴露于结核分枝杆菌后的结果，但仍然知之甚少。粘膜 相关不变T（MAIT）细胞是一种在人类中普遍存在的先天性样T细胞亚群，并在人类中富集。 气道。人MAIT细胞通过表达半恒定TCRα链TRAV 1-TRAV 2来定义。 2/TRAJ 12/20/33及其受非多态性MHC I类分子、MHC相关蛋白1的限制 （MR1）。MAIT细胞识别结核分枝杆菌，并可被来自核黄素的小有机分子激活。 生物合成途径我们已经证明，MR 1限制性T细胞可以使用不是TRAV 1 -2的TCR， 可以识别不能产生核黄素的生物{Meermeier，2016}。因此，我们定义MAIT 细胞作为MR 1限制性T细胞（MR 1 T）的子集。此外，我们发现，并非所有的MR 1 T都可以定义为 基于与已知MAIT激动剂/MR 1配体5-（2-氧代亚丙基氨基）-6-D- 核糖基氨基尿嘧啶（5-OP-RU），因为它们可以基于它们对微生物的MR 1依赖性反应来定义 感染和结合到交替的MR 1四聚体。我们为新型分枝杆菌衍生的MR 1 抗原，并证明肺中的MR 1 Ts的特点是寡克隆富集，可能 由这些抗原驱动。最后，我们发现肺部驻留MR 1 Ts具有抗微生物效应能力。 这些发现提出了一种有趣的可能性，即肺内结核反应性MR 1 Ts可能在肺结核的发病中发挥专门的作用。 在早期发现和控制结核分枝杆菌感染方面的作用。具体来说，这可能是释放的结果 促炎性细胞因子如IFN-γ，以及它们的直接抗微生物活性。在本申请中， 我们将使用胸部成像（PET/CT或传统X线摄影）来确定艾滋病毒感染者的健康状况， 暴露于Mtb后未感染的个体。临床TB患者将根据症状 疾病、异常CXR和培养阳性。在CXR、PET/CT阴性的无症状个体中 将用于对耐药（PET/CT阴性）与亚临床疾病患者进行分类 (PET/CT阳性）。我们假设肺部MR 1 Ts有能力识别和控制 结核分枝杆菌感染将与良好的临床结果相关。 在这个应用中，我们将解决以下问题：1）什么是流行和效应 功能MR 1 T细胞在肺和外周血暴露于结核分枝杆菌和艾滋病毒的设置？（二） MR 1 T TCR的使用和配体识别与暴露于结核分枝杆菌后的结局之间的关系是什么？ 3)MR 1 T细胞如何控制结核分枝杆菌感染？ 最终，该项目的工作将支持MR 1 T细胞靶向疫苗和免疫疗法 作为在暴露于Mtb后提高对疾病的抵抗力的手段。

Project Summary In humans, aerosol exposure to Mycobacterium tuberculosis (Mtb) results is disparate outcomes, ranging from no-infection and/or clearance, to progressive disease. Lung-resident, immune effectors likely play a critical role is determining the outcome following exposure to Mtb, yet remain poorly understood. Mucosal associated invariant T (MAIT) cells are an innate-like T cell subset prevalent in humans and enriched in the airway. Human MAIT cells have been defined by the expression of the semi-invariant TCRα chain TRAV1- 2/TRAJ12/20/33 and their restriction by the non-polymorphic MHC class I-like molecule, MHC-related protein 1 (MR1). MAIT cells recognize Mtb and can be activated by small organic molecules, derived from the riboflavin biosynthesis pathway. We have shown that MR1-restricted T cells can use TCRs that are not TRAV1-2, and can recognize organisms that cannot produce riboflavin {Meermeier, 2016}. Consequently, we define MAIT cells as a subset of MR1-restricted T cells (MR1Ts). Furthermore, we find that not all MR1Ts can be defined based on MR1 tetramer bound to the known MAIT agonist / MR1 ligand 5-(2-oxopropylideneamino)-6-D- ribitylaminouracil (5-OP-RU), in that they can be defined based on their MR1-dependent response to microbial infection and binding to alternate MR1 tetramers. We provide evidence for novel, mycobacterially-derived MR1 antigens, and demonstrate that MR1Ts in the lung are characterized by oligoclonal enrichments, possibly driven by these antigens. Finally, we find that lung-resident MR1Ts have anti-microbial effector capacity. These findings raise the intriguing possibility that lung resident, Mtb-reactive, MR1Ts could play a specialized role in the early detection and control of infection due to Mtb. Specifically, this could be the result of the release of pro-inflammatory cytokines such as IFN-γ, as well as by their direct anti-microbial activity. In this application, we will use thoracic imaging (PET/CT or traditional radiography) to define the health status of HIV infected and uninfected individuals following exposure to Mtb. Those with clinical TB will be defined by symptomatic disease, abnormal CXR, and culture positivity. Among asymptomatic individuals with a negative CXR, PET/CT will be used to categorize those who are resistant (PET/CT negative) vs those with subclinical disease (PET/CT positive). We hypothesize that lung resident MR1Ts with the capacity to recognize and control infection with Mtb will be associated with favorable clinical outcomes. In this application, we will address the following questions: 1) What is the prevalence and effector function of MR1T cells in the lung and peripheral blood following exposure to Mtb and in the setting of HIV? 2) What is the relationship of MR1T TCR usage and ligand discrimination to outcomes following exposure to Mtb? 3) How might MR1T cells control infection with Mtb? Ultimately, the work from this project would support MR1T cell targeted vaccines and immune-therapies as a means to improve resistance to disease following exposure to Mtb.