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。我们最近报道了NKT细胞确实存在于哮喘受试者的肺中，产生高水平的IL-4和IL-13。在这个计划中，我们首先要研究NKT细胞在诱导气道高反应性中的作用，其次我们要研究NKT细胞活化如何影响T细胞极化和耐受，第三，我们要研究NKT和调节性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TH 2细胞因子，IL-4和IL-13的作用。NKT细胞通过其有限的TCR库识别由CD Id呈递的糖脂。树突状细胞表达CD Id，我们的初步数据表明NKT细胞和DC之间的相互作用对于诱导AHR是必需的。我们希望研究DC在NKT细胞活化/极化中的作用，特别是共刺激分子如ICOS、OX-40和PD-1在诱导NKT细胞中的作用。我们的初步数据表明，虽然幼稚和活化的NKT细胞都表达高水平的ICOS和OX- 40，但PD-1仅在CD 4 + NKT细胞上表达。在项目的第二部分中，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组的严重气道病理。更好地理解导致T细胞耐受的机制是治疗疾病的有价值的方法。我们的初步数据表明，激活后，NKT细胞可以潜在地打破T细胞耐受，然而，驱动NKT细胞激活或调节的信号尚未确定。我们将研究共刺激分子、抗原呈递细胞和细胞因子在活化的NKT细胞消除耐受中的作用。在第三部分中，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AHR调节中的重要性。项目的三个部分最终将通过分析给予NKT细胞的信号是否导致极化NKT细胞的发展而连接起来，其作用将在体内和体外进行研究。

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.