CD1d-restricted T Cell Self-antigens and Infection

CD1d 限制性 T 细胞自身抗原与感染

• 批准号: 7215554
• 负责人: Michael B. Brenner
• 金额: $ 40.42万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-07-01 至 2010-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7215554
• 关键词: Acute-Phase Reaction; Address; Antigen Presentation; Antigens; Apolipoprotein E; Autoantigens; B-Lymphocytes; Binding; Cell Line; Condition; Dendritic Cells; Development; Disease; Employee Strikes; High Density Lipoproteins; Host Defense; Human; Infection; Inflammation; Inflammatory; Length; Lipids; Lipoproteins; Low Density Lipoprotein Receptor; Low-Density Lipoproteins; Lysosomes; Metabolism; Mus; NK Cell Activation; Pathway interactions; Proteins; Research Personnel; Role; Route; Saposins; Serum; Source; Surface; T-Cell Activation; T-Lymphocyte; Very low density lipoprotein; antigen binding; cytokine; extracellular; in vivo; killer T cell; macrophage; microbial; monocyte; programs; trafficking

DESCRIPTION (provided by applicant): Natural killer T (NKT) cells recognize CD1d presented lipid antigens. NKT cells have been strongly implicated in host defense to microbial infection due to their ability to rapidly secrete large amounts of cytokines and their influence on the activation of NK cells, macrophages, dendritic cells, B cells and T cells. Except for the striking evidence that aGalCer can pharmacologically activate NKT cells, little is known about the antigens that activate NKT cells physiologically in vivo. Most evidence suggests that CD1d molecules present self-lipid antigens for the development and activation of NKT cells. In mice, self-antigens for Va14 invariant NKT cells are acquired by CD1d molecules that traffic to lysosomes and loading is dependent on saposins. In contrast, the self-antigens for diverse TCR NKT cells may be acquired in the ER. These features are different for human Vot24 invariant NKT cells, as they are stimulated by CD1d molecules that do not traffic through lysosomes and are not saposin dependent. It is assumed that self-antigens are made by CD1d+ ARC and thus are considered endogenous. However, we have now determined that CD1d presented self-lipids also are acquired from extracellular sources where lipids are mainly bound to iipoproteins such as apoE. Thus, we separate endogenous and exogenous pathways of CD1d self-antigen presentation. Here, we propose to identify the self-lipid antigens that bind to CD1d along the secretory route or when trafficking through endosomal compartments and determine which are stimulatory for NKT cells (Aim 1). Because several lines of evidence suggest that important differences exist, we will compare the CD1d selfantigens and their ability to stimulate NKT cells in mice with those in humans (Aim 2). We will then determine the self-antigens acquired by the newly appreciated apoE dependent exogenous pathway (Aim 3). Since lipid and lipoprotein metabolism are changed profoundly in the acute phase reaction during infection, we will determine how endogenously and exogenously acquired CD1d presented self-lipids are altered in inflammation (Aim 4). These studies seek to address the fundamental mechanisms and unanswered questions regarding the self-antigens that activate CD Id-restricted NKT. This has significance for understanding the function of NKT cells and is important for host defense to infection and other diseases.

描述（由申请人提供）：自然杀伤T（NKT）细胞识别CD1d呈递的脂质抗原。NKT细胞由于其快速分泌大量细胞因子的能力及其对NK细胞、巨噬细胞、树突细胞、B细胞和T细胞的活化的影响而强烈地参与宿主对微生物感染的防御。除了aGalCer可以间接激活NKT细胞的显著证据之外，关于在体内生理上激活NKT细胞的抗原知之甚少。大多数证据表明，CD1d分子为NKT细胞的发育和活化呈现自身脂质抗原。在小鼠中，Va14不变NKT细胞的自身抗原通过CD1d分子获得，该分子运输到溶酶体并且负载依赖于saposins。相反，不同TCR NKT细胞的自身抗原可在ER中获得。这些特征对于人Vot24不变NKT细胞是不同的，因为它们被不通过溶酶体运输并且不依赖saposin的CD1d分子刺激。假设自身抗原由CD1d+ ARC产生，因此被认为是内源性的。然而，我们现在已经确定，CD1d呈递的自身脂质也是从细胞外来源获得的，其中脂质主要与脂蛋白如apoE结合。因此，我们分离的内源性和外源性途径的CD1d自身抗原呈递。 在这里，我们建议确定自身脂质抗原，结合CD 1d沿着分泌途径或通过内体室运输时，并确定哪些是刺激NKT细胞（目的1）。因为有几条证据表明存在重要的差异，我们将比较CD1d自身抗原及其刺激小鼠和人类NKT细胞的能力（目的2）。然后，我们将确定通过新近认识到的apoE依赖性外源性途径获得的自身抗原（目的3）。由于脂质和脂蛋白代谢在感染期间的急性期反应中发生了深刻的变化，我们将确定内源性和外源性获得的CD1d呈递的自身脂质在炎症中是如何改变的（目的4）。这些研究试图解决关于激活CD Id限制性NKT的自身抗原的基本机制和未回答的问题。这对于理解NKT细胞的功能具有重要意义，并且对于宿主防御感染和其他疾病具有重要意义。