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: 8819199
• 负责人: Louise M. D'Cruz
• 金额: $ 24.9万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 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 2016-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8819199
• 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; abstracting; 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

Project Summary/Abstract: 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 the 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.

项目摘要/摘要： 自然杀伤 T (NKT) 细胞是免疫系统的先天性细胞，能够快速激活和产生 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；并在 检测并消除恶性细胞。虽然特定的转录因子和信号分子具有 已被证明对于 NKT 细胞的早期发育非常重要，其所需的许多因素 外周的成熟、维持和激活仍然未知。我最近表明 转录因子 HEB 对于 NKT 细胞的发育至关重要，并且还表明转录调节因子 Id2 控制肺和肝等组织中 NKT 细胞的存活。该提案将阐明 E 的作用 蛋白和 Id 蛋白在这种重要细胞类型的分化中的作用。我将探讨 NKT 细胞如何应对 急性与慢性感染以及与其激活与无反应性沉默相关的因素。我会 研究感染期间 NKT 细胞激活如何影响其他适应性免疫细胞，即 CD8+ T 细胞。到 为此我提出以下目标。目标 1：检查 Id2 和 Id3 在 NKT 细胞中的作用 分化以及这些细胞的稳态和激活。我目前的数据表明转录 调节因子 Id2- 和 Id3- 在 NKT 细胞分化过程中以及在成熟 NKT 细胞中相互表达 周围组织。我建议，使用最近生成的 Id2 和 Id3 报告线，以及 Id2 和 Id3- 缺陷细胞系，以检查这些转录调节因子如何影响 NKT 细胞的成熟和激活。目标 2： 了解 NKT 细胞对急性和慢性感染的反应。 NKT 细胞产生大量的 细胞因子激活后，并表现出细胞毒功能。这种激活爆发之后是无能的 细胞经历凋亡或保持增殖抵抗的阶段。尚不清楚这种无反应性是否 NKT 细胞在慢性感染期间发生阶段，或者实际上 NKT 细胞是否由于持续的感染而保留活性 抗原刺激。使用 LCMV 作为急性和慢性感染的模型，我将检查 NKT 细胞反应 持续的抗原刺激。此外，我建议使用微阵列基因表达分析来检查 NKT 细胞在感染期间过渡到无反应阶段时发生的分子变化。 这些研究的结果将有助于了解胸腺中 NKT 细胞的发育和 外周组织及其在急性和慢性感染中激活所需的因子。目标 3：定义 NKT 细胞如何影响 CD8+ T 细胞效应器和激活后的记忆形成。当 NKT 细胞产生 大量炎症细胞因子被激活后，如何影响 CD8+ 效应器和记忆 T 细胞的形成， 它们在感染过程中对炎症环境极其敏感，目前尚不清楚。使用 NKT细胞缺陷小鼠和T细胞受体转基因小鼠，我将检查效应和记忆CD8+ T细胞 感染期间缺乏 NKT 细胞的情况下的形成和功能。这些研究将有助于定义 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 对于未来的疫苗设计和功效很重要。