Role of NKT cells in airway hyperreactivity & tolerance

描述（由申请人提供）：本研究的长期目标是增加我们对过敏性肺病和哮喘发病机制中涉及的免疫机制的理解。我们将研究NKT细胞影响气道高反应性（AHR）诱导的机制，AHR是哮喘的主要特征。我们最近报道NKT细胞确实存在于哮喘患者的肺部，产生高水平的IL-4和IL-13。在本提案中，首先我们想要研究NKT细胞在诱导气道高反应性中的作用，其次我们想要研究NKT细胞激活如何影响T细胞极化和耐受性，第三，我们想要研究NKT与调节性T细胞之间的相互作用。在第一部分中，我们将研究NKT细胞和细胞因子，特别是TH2细胞因子，IL-4和IL-13的作用。NKT细胞通过其有限的TCR库识别CD Id呈现的糖脂。树突状细胞表达CD Id，我们的初步数据表明，NKT细胞和dc之间的相互作用是诱导AHR的必要条件。我们想研究DC在NKT细胞激活/极化中的作用，特别是ICOS、OX-40、PD-1等共刺激分子在NKT细胞诱导中的作用。我们的初步数据表明，虽然初始和激活的NKT细胞都表达高水平的ICOS和OX- 40，但PD-1仅在CD4+ NKT细胞上表达。在项目的第二部分，我们将研究NKT细胞在T细胞耐受中的作用。正如我们所知，特应性和非特应性个体都不断暴露于空气过敏原，导致前者的保护和后者的严重气道病理。更好地了解导致T细胞耐受的机制是治疗疾病的一个有价值的方法。我们的初步数据表明，激活后，NKT细胞可能会破坏T细胞的耐受性，然而，驱动NKT细胞激活或调节的信号尚未明确。我们将研究共刺激分子、抗原提呈细胞和细胞因子在激活的NKT细胞消除耐受性中的作用。在第三部分，我们将研究NKT细胞和调节性T细胞之间的潜在相互作用，包括调节性T细胞在调节AHR中的重要性。通过分析给予NKT细胞的信号是否会导致极化NKT细胞的发育，最终将项目的三个部分联系起来，并在体内和体外研究其作用。

DESCRIPTION (provided by applicant): The long term goal of this study is to increase our understanding of the immune mechanisms involved in the pathogenesis of allergic lung disease and asthma. We are going to study the mechanisms by which NKT cells influence the induction of airway hyperreactivity (AHR), a cardinal feature of asthma. We recently reported that NKT cells are indeed present in the lungs of asthmatic subjects, produce high level of IL-4 & IL-13. In this proposal, first we would like to study the role of NKT cells in induction of airwayhyperreactivity, second we would like to investigate how NKT cell activation can influence T cell polarization and tolerance, and third, we would like to study the interactions between NKT and regulatory T cells. In the first part we will study the role of NKT cells and cytokines in particular TH2 cytokines, IL-4 and IL-13. NKT cells through their limited TCR repertoire recognize glycolipids presented by CD Id. Dendritic cells express CD Id and our preliminary data indicated that the interactions between NKT cells and DCs are essential for induction of AHR. We would like to study the role DC in activation/polarization of NKT cells, in particular role of costimulatory molecules such as ICOS, OX-40 and PD-1 in induction of NKT cells. Our preliminary data indicated that while naive and activated NKT cells, both express high levels of ICOS and OX- 40, PD-1 is only expressed on CD4+ NKT cells. In the second part of the projects we will investigate the role of NKT cells in T cell tolerance. As we know, both atopic and non-atopic individuals are constantly exposed to aeroallergens, leading to protection in the former and severe airway pathology in the later group. A better understanding of the mechanisms resulting in T cell tolerance is a valuable approach towards therapy for diseases. Our preliminary data suggest that upon activation, NKT cells can potentially break T cell tolerance, however, the signals that drive NKT cells into activation or regulation, are as yet undefined. We will study the role of costimulatory molecules, antigen presenting cells and cytokines in abrogation of tolerance by activated NKT cells. In the third part, we will investigate the potential interactions between NKT cells and regulatory T cells, including the importance of regulatory T cells in regulation of AHR. The three parts of project will finally be connected by analyzing whether signals given to NKT cells result in the development of polarized NKT cells whose actions will be studied in vivo and in vitro.