Human MAIT celis in airway mucosal immune responses to intracellular infections

描述（由申请人提供）：人体气道是一个复杂的免疫器官，反映了其在宿主对空气传播感染的反应中的核心作用。在气道内发现的先天性T细胞有可能在识别这些病原体、控制它们以及获得适应性免疫中发挥关键作用。人粘膜相关不变T（MAIT）细胞是在所有人中发现的独特T细胞群，其特征在于使用半不变T细胞受体（TCR; Va 7.2）、依赖于非经典（HLA-Ib）分子MRI以及它们的快速效应子功能。我们最近发现MAIT细胞能够识别细菌感染的上皮细胞，并且在人气道和肺实质中高度富集。此外，在分析MAIT细胞在结核分枝杆菌（Mtb）感染者中的作用时，我们发现这些细胞在活动性而非潜伏性结核病患者中几乎不存在。因此，MAIT细胞在人气道中的位置，连同它们快速响应细菌感染的上皮细胞的能力，使这些细胞在控制细胞内感染中发挥关键作用。该建议的具体目标是描述这些细胞在人类宿主对空气传播感染的反应中的作用。首先，虽然我们已经发现MRI限制性MAIT细胞能够识别广泛的病原体，但配体和/或病原体识别的多样性尚不清楚。因此，在第一个目标中，MAIT细胞识别的病原体的全谱将关于TCR使用来表征。第二，我们发现人原代肺上皮细胞可以产生INOS以响应IFN-γ以及直接的T细胞接触。因此，在第二个目标中，我们将确定MAIT细胞对上皮iNOS的产生和随后的细菌控制的贡献。最后，在我们对人气道免疫细胞的分析中，我们观察到在不存在DC的情况下MAIT细胞的存在。因此，我们推测MAIT细胞的一个功能是“许可”肺上皮细胞，导致DC的募集和成熟。第三个目标是确定MAIT细胞与气道上皮细胞和树突状细胞的关系。

DESCRIPTION (provided by applicant): The human airway is a complex immune organ, reflecting its central role in the host response to airborne infection. Innate T cells found within the airway have the potential to play a critical role in the recognition of these pathogens, in their control, and in the acquisition of adaptive immunity. Human mucosal associated invariant T (MAIT) cells are a unique T cell population found in all humans that are characterized by the use of a semi-invariant T cell receptor (TCR; Va7.2), dependence on the non-classical (HLA-lb) molecule MRI, and their rapid effector function. We have recently found MAIT cells to be capable of the recognition of bacterially-infected epithelial cells, and to be highly enriched in the human airway and lung parenchyma. Furthermore, in an analysis of the role of MAIT cells in those infected with Mycobacterium tuberculosis (Mtb), we found these cells to be virtually absent in those with active but not latent tuberculosis. As a result, the location of MAIT cells in the human airway, in conjunction with their ability to rapidly respond to bacterially infected epithelial cells positions these cells to play a critical role in the control of intracellular infection. The specific aims of this proposal are designed to delineate the role of these cells in the human host response to airborne infection. First, while we have found that MRI-restricted MAIT cells are capable of recognizing a broad array of pathogens, the diversity of ligand and/or pathogen recognition is not known. As a result, in the first aim the full spectrum of pathogens recognized by MAIT cells will be characterized with regard to TCR usage. Second, we have found that human primary lung epithelial cells can produce INOS both in response to IFN-gamma as well as direct T cell contact. Consequently, in the second aim we will determine the contribution of MAIT cells to the production of epithelial iNOS and consequent bacterial control. Finally, in our analysis of human airway immune cells, we have observed the presence of MAIT cells in the absence of DC. Consequently, we postulate that one function of MAIT cells is to "license" lung epithelial cells resulting in the recruitment and maturation of DC. The third aim will determine the relationship of MAIT cells with airway epithelium and dendritic cells.