Regulation of Natural Killer T cell maturation, homeostasis and activation

描述(申请人提供)：自然杀伤T细胞(NKT)是免疫系统的先天细胞，能够迅速激活和产生细胞因子。NKT细胞已被证明在细菌、病毒和真菌感染期间有反应，并在自身免疫性疾病中发挥作用；在镰状细胞疾病和哮喘中造成肺组织损害；以及在检测和消除恶性细胞方面发挥作用。虽然特定的转录因子和信号分子对NKT细胞的早期发育很重要，但其成熟、维持和外周激活所需的许多因子仍不清楚。最近，我发现转录因子heb对NKT细胞的发育是必不可少的，还表明转录调控因子Id2控制着NKT细胞在肺和肝脏等组织中的存活。这一建议将阐明E蛋白和TE ID蛋白在这一重要细胞类型分化中的作用。我将探索NKT细胞如何对 急性感染与慢性感染及其激活与失能沉默的相关因素。我将研究感染期间NKT细胞的激活如何影响其他适应性免疫细胞，即CD8+T细胞。为此，我提出以下目标。目的1：研究Id2和Id3在NKT细胞分化过程中的作用，以及在NKT细胞动态平衡和活化中的作用。我目前的数据表明，转录调控因子Id2和Id3在NKT细胞分化过程中和周围组织中成熟的NKT细胞中相互表达。我建议，使用最近生成的Id2和Id3报告行，以及Id2和Id3缺失的报告行 研究这些转录调控因子如何影响NKT细胞的成熟和激活。目的2：了解NKT细胞对急性和慢性感染的反应。NKT细胞在激活后产生大量的细胞因子，并表现出细胞毒功能。这种激活爆发之后是一个无能阶段，在这个阶段，细胞经历凋亡或保持对增殖的抵抗。目前尚不清楚在慢性感染期间NKT细胞是否发生了这种无能阶段，或者NKT细胞是否由于持续的抗原而保持活性。 刺激。使用LCMV作为急性和慢性感染的模型，我将检测NKT细胞对持续抗原刺激的反应。此外，利用微阵列基因表达分析，我建议检查NKT细胞在感染期间通过无反应阶段时发生的分子变化。这些研究结果将有助于了解NKT细胞在胸腺和外周组织中的发育，以及在急性和慢性感染中激活NKT细胞所需的因素。目的3：明确NKT细胞激活后对CD8+T细胞效应和记忆形成的影响。虽然NKT细胞在激活时会产生许多炎性细胞因子，但这如何影响CD8+效应器和记忆性T细胞的形成，这两个细胞在感染过程中对炎症环境非常敏感，目前还完全不清楚。我将利用NKT细胞缺陷小鼠和T细胞受体转基因小鼠，在感染过程中没有NKT细胞的情况下，检测效应器和记忆性CD8+T细胞的形成和功能。这些研究将有助于确定NKT细胞在急性感染中的重要性，并将评估这些细胞如何影响免疫记忆，免疫记忆是免疫系统的重要组成部分，是防止后续感染所必需的。这些研究将对未来的疫苗设计和疗效具有重要意义。项目简介：自然杀伤T细胞是免疫系统中的一种细胞，具有在激活时迅速产生一系列细胞因子的能力，因此被认为是弥合先天免疫反应和获得性免疫反应之间的桥梁。这项研究将检验自然杀手T细胞分化、动态平衡以及它们在急性和慢性感染中激活所必需的因素。此外，这项研究将研究自然杀伤T细胞如何与免疫系统的其他细胞相互作用和影响，以提供对疾病的保护。最近的研究表明，这些细胞在自身免疫、癌症和肺部疾病中发挥着重要作用，因此研究这些细胞是如何在周围组织中维持的以及它们激活所需的因素将具有生物学和医学价值。

DESCRIPTION (provided by applicant): Natural Killer T (NKT) cells are innate-like cells of the immune system, capable of swift activation and production of cytokines. NKT cells have been shown to respond during bacterial, viral and fungal infections, as well as playing roles in autoimmune disease; causing damage to lung tissue in sickle cell disease and in asthma; and in the detection and elimination of malignant cells. While specific transcription factors and signaling molecules have been shown to be important for early stage development of NKT cells, many of the factors required for their maturation, maintenance and activation in the periphery remain unknown. I recently showed that the transcription factor HEB is essential for NKT cell development and also showed that the transcriptional regulator Id2 controls survival of NKT cells in tissues such as lung and liver. This proposal will illuminate the role of E proteins and te Id proteins in differentiation of this important cell type. I will explore how NKT cells respond to acute versus chronic infection and the factors associated with their activation versus anergic silencing. I will examine how NKT cell activation during infection affects other adaptive immune cells, namely CD8+ T cells. To this end I propose the following aims. Aim 1: Examine the role of both Id2 and Id3 during NKT cell differentiation and in the homeostasis and activation of these cells. My current data suggest the transcriptional regulators Id2- and Id3- are reciprocally expressed during NKT cell differentiation and in mature NKT cells in peripheral tissues. I propose, using recently generated reporter lines for Id2 and Id3, as well as Id2 and Id3- deficient lines, to examine how these transcriptional regulators impact NKT cell maturation and activation. Aim 2: Understanding NKT cell response to acute and chronic infection. NKT cells produce prodigious quantities of cytokines upon activation, as well as exhibiting cytotoxic function. This activation burst is followed by an anergic phase in which cells undergo apoptosis or remain resistant to proliferation. It is not known whether this anergic phase occurs in NKT cells during chronic infection or indeed whether NKT cells retain activity due to continual antigen stimulation. Using LCMV as a model of acute and chronic infection, I will examine the NKT cell response to persistent antigen stimulation. Furthermore, using microarray gene-expression analysis, I propose to examine the molecular changes that occur in NKT cells as they transition through the unresponsive phase during infection. The results from these studies will be useful in understanding development of NKT cells in the thymus and peripheral tissues as well as the factors required for their activation in acute and chronic infection. Aim 3: Define how NKT cells affect CD8+ T cell effector and memory formation upon activation. While NKT cells produce numerous inflammatory cytokines when activated, how this affects CD8+ effector and memory T cell formation, which are exquisitely sensitive to the inflammatory environment during infection, is completely unknown. Using NKT cell-deficient mice and T cell receptor-transgenic mice, I will examine effector and memory CD8+ T cell formation and function in the absence of NKT cells during infection. These studies will help to define the importance of NKT cells in acute infection and will assess how these cells influence immunological memory, an essential component of the immune system, required for protection from subsequent infection. These studies will be important for future vaccine design and efficacy. Project Narrative: Natural Killer T cells are elie cells of the immune system armed with the ability to rapidly produce an array of cytokines upon activation, and as such are thought to bridge the gap between the innate and adaptive immune responses. The research proposed here will examine the factors necessary for Natural Killer T cell differentiation, homeostasis as well as for their activation in acute and chronic infection. Furthermore, this research will examine how Natural Killer T cells interact with and influence other cells of the immune system to provide protection from disease. Recent studies show an important role for these cells in autoimmunity, cancer and lung disease, and therefore study of how these cells are maintained in peripheral tissues and the factors required for their activation will be of value to both biology and medicine.