CD1d-restricted T Cell Self-antigens and Infection

描述(申请人提供)：自然杀伤T(NKT)细胞识别CD1d提呈的脂类抗原。由于NKT细胞能够快速分泌大量细胞因子，并影响NK细胞、巨噬细胞、树突状细胞、B细胞和T细胞的活化，因此NKT细胞在宿主抵御微生物感染方面具有重要意义。除了引人注目的证据表明，aGalCer可以在药物上激活NKT细胞外，人们对体内生理激活NKT细胞的抗原知之甚少。大多数证据表明，CD1d分子为NKT细胞的发育和激活提供自体脂类抗原。在小鼠中，Va14不变NKT细胞的自身抗原是由CD1d分子获得的，CD1d分子运输到溶酶体，负载依赖于皂苷。相反，不同TCR NKT细胞的自身抗原可能是在内质网中获得的。这些特征对于人类Vot24不变的NKT细胞是不同的，因为它们受到CD1d分子的刺激，CD1d分子不通过溶酶体运输，也不依赖于皂苷。假设自身抗原是由CD1d+ARC产生的，因此被认为是内源性的。然而，我们现在已经确定CD1d呈递的自体脂类也是从细胞外来源获得的，其中脂类主要与载脂蛋白E等脂蛋白结合。因此，我们分离了CD1d自身抗原呈递的内源性和外源性途径。 在这里，我们建议识别与CD1d结合的自体脂类抗原，沿着分泌途径或当通过内体隔室运输时，并确定哪些对NKT细胞具有刺激作用(目标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(目标2)。然后，我们将确定新认识的载脂蛋白E依赖的外源途径(目标3)获得的自身抗原。由于在感染期间的急性期反应中，脂类和脂蛋白代谢发生了深刻的变化，我们将确定内源性和外源性获得的CD1d呈现的自身脂类在炎症中是如何改变的(目标4)。这些研究试图解决有关自身抗原激活CD ID限制性NKT的基本机制和尚未回答的问题。这对了解NKT细胞的功能具有重要意义，对宿主抵御感染等疾病具有重要意义。

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.