Regulation of Natural Killer T cell maturation, homeostasis and activation

自然杀伤 T 细胞成熟、稳态和激活的调节

• 批准号: 8382892
• 负责人: Louise M. D'Cruz
• 金额: $ 9万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-05-10 至 2013-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8382892
• 关键词: Acute; Address; Affect; Antigens; Apoptosis; Asthma; Autoimmune Diseases; Autoimmunity; Bacterial Infections; Biology; CD8-Positive T-Lymphocytes; CD8B1 gene; Cancerous; Cell Maturation; Cells; Cellular biology; Chronic; Chronic Disease; Data; Detection; Development; Disease; E protein; Environment; Exhibits; Future; Gene Expression Microarray Analysis; Glycolipids; Goals; Homeostasis; Hour; Human; Immune; Immune response; Immune system; Immunity; Immunologic Memory; Infection; Inflammatory; Interferons; Life; Liver; Lung; Lung diseases; Lymphocyte; Lymphocytic choriomeningitis virus; MHC Class I Genes; Maintenance; Malignant Neoplasms; Medicine; Memory; Modeling; Molecular; Mus; Mycoses; Pattern; Peripheral; Phase; Phenotype; Play; Process; Production; Proteins; Regulation; Reporter; Reporting; Research; Research Proposals; Resistance; Resolution; Role; Sickle Cell Anemia; Signaling Molecule; Staging; Structure of parenchyma of lung; Surface; T cell anergy; T cell differentiation; T cell response; T memory cell; T-Cell Activation; T-Cell Development; T-Cell Receptor; T-Lymphocyte; Thromboplastin; Thymus Gland; Tissues; Transgenic Mice; Vaccine Design; Virus Diseases; Work; anergy; arm; cancer cell; cell type; cytokine; cytotoxic; cytotoxicity; disorder prevention; helix-loop-helix protein differentiation inhibitor; killer T cell; precursor cell; response; transcription factor; vaccine efficacy

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.

描述（由申请人提供）：自然杀伤T（NKT）细胞是免疫系统的先天性样细胞，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做出反应，以及在自身免疫性疾病中发挥作用;在镰状细胞病和哮喘中对肺组织造成损害;以及在检测和消除恶性细胞中。虽然特定的转录因子和信号分子已被证明对NKT细胞的早期发育是重要的，但它们在外周中成熟、维持和活化所需的许多因子仍然未知。我最近表明，转录因子HEB是NKT细胞发育所必需的，也表明转录调节因子Id 2控制NKT细胞在肺和肝等组织中的存活。这一提议将阐明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 急性与慢性感染以及与它们的激活与无反应性沉默相关的因素。我将研究感染期间NKT细胞活化如何影响其他适应性免疫细胞，即CD 8 + T细胞。为此，我提出以下目标。目的1：研究Id 2和Id 3在NKT细胞分化过程中以及在这些细胞的稳态和活化中的作用。我目前的数据表明，转录调节因子Id 2-和Id 3-在NKT细胞分化过程中和外周组织中的成熟NKT细胞中不稳定表达。我建议，使用最近生成的Id 2和Id 3的报告细胞系，以及Id 2和Id 3缺陷的报告细胞系， 细胞系，以研究这些转录调节因子如何影响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细胞在活化后产生大量的细胞因子，并表现出细胞毒性功能。这种激活爆发之后是无反应性阶段，其中细胞经历凋亡或保持对增殖的抗性。目前尚不清楚在慢性感染期间NKT细胞是否会出现这种无反应性阶段，或者NKT细胞是否确实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，我将检查NKT细胞对持续抗原刺激的反应。此外，使用微阵列基因表达分析，我建议检查发生在NKT细胞的分子变化，因为它们通过感染期间的无反应阶段的过渡。这些研究的结果将有助于了解胸腺和外周组织中NKT细胞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：确定NKT细胞如何影响活化后的CD 8 + T细胞效应和记忆形成。虽然NKT细胞在激活时产生许多炎性细胞因子，但这如何影响CD 8+效应和记忆T细胞的形成，这些细胞在感染期间对炎症环境非常敏感，这是完全未知的。使用NKT细胞缺陷小鼠和T细胞受体转基因小鼠，我将检查在感染过程中NKT细胞缺失的情况下效应和记忆CD 8 + 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，是防止随后感染所必需的。这些研究对未来的疫苗设计和有效性具有重要意义。项目叙述：自然杀伤T细胞是免疫系统的elie细胞，具有在激活时快速产生一系列细胞因子的能力，因此被认为是先天性和适应性免疫应答之间的差距的桥梁。本文提出的研究将研究自然杀伤T细胞分化，稳态以及它们在急性和慢性感染中激活所必需的因素。此外，这项研究还将研究自然杀伤T细胞如何与免疫系统的其他细胞相互作用并影响它们，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，癌症和肺部疾病中起着重要作用，因此研究这些细胞如何维持在外周组织中以及它们激活所需的因素对生物学和医学都有价值。