PLZF expression in adipose resident natural killer T cells

项目摘要 脂肪组织是免疫系统和新陈代谢途径相交的地方。脂肪细胞现在 被认为是脂类的抗原提呈细胞，可能通过 CD1d。NKT细胞是免疫系统的强大调节器，能够调节其他细胞的功能 细胞类型在很大程度上取决于它们快速产生大量各种细胞因子的能力。最新数据 显示脂肪滞留的NKT细胞(arNKT细胞)调节饮食诱导的体重增加和影响 新陈代谢。当进食热量平衡的饮食时，arNKT细胞似乎鼓励脂肪细胞维持 健康的组织环境，预防胰岛素抵抗。 NKT细胞几乎所有的先天功能都依赖于BTB-ZF转录因子PLZF (Zbtb16)。因此，arNKT细胞不表达PLZF是令人惊讶的。据我们所知，这是唯一的 不连续表达转录因子的NKT细胞群。慢性炎症是 与体重增加和随后的代谢性疾病有关。研究表明，ArNKT细胞可诱导抗-NKT 炎症反应既通过调节巨噬细胞的功能，也通过影响频率、增殖 以及表达FoxP3的Tregs的功能。我们认为PLZF表达的改变会影响这些arNKT 细胞功能反过来又会改变白色脂肪组织的新陈代谢。我们的研究将确定 在arNKT细胞中PLZF表达的变化改变了它们控制肥胖和代谢变化的能力。 我们将使用一系列创新的转基因小鼠模型，以允许不同水平的 PLZF表达式。我们假设PLZF蛋白水平对arNKT细胞功能的控制是必不可少的。 如果这些水平发生变化，肥胖和代谢性疾病的发病率将会增加。支持这一点的数据 结论将导致未来的研究，以确定人类PLZF表达的可变性是否可能是一种 导致肥胖的因素。重要的是，对无法正常运行的arNKT细胞的分析有望 揭示有关arNKT细胞正常运作机制的新信息。

Project Summary Adipose tissue is a site where the immune system and metabolic pathways intersect. Adipocytes are now recognized as antigen presenting cells for lipids and likely directly activate natural killer T cells (NKT cells) via CD1d. NKT cells are potent modulators of the immune system that are able to regulate the function of other cell types largely by their capacity to rapidly produce large amounts of a wide variety of cytokines. Recent data show that adipose resident NKT cells (arNKT cells) modulate diet-induced weight gain and influence metabolism. When eating a calorically balanced diet, arNKT cells appear to encourage adipocytes to maintain a healthy tissue environment and prevent insulin resistance. Nearly all of the innate-like functions of NKT cells are dependent upon the BTB-ZF transcription factor, PLZF (zbtb16). Therefore, it is surprising that arNKT cells do not express PLZF. To our knowledge, this is the only population of NKT cells that does not continuously express the transcription factor. Chronic inflammation is associated with weight gain and subsequent metabolic disease. arNKT cells were shown to induce an anti- inflammatory response both by modulating macrophage functions and by impacting the frequency, proliferation and function of FoxP3-expressing Tregs. We propose that altered PLZF expression will impact these arNKT cell functions, which in turn, will alter the metabolism of white adipose tissue. Our studies will determine if changes in PLZF expression in arNKT cells alters their ability to control obesity and metabolic changes. We will use an innovative array of genetically modified mouse models that allow for variation in the levels of PLZF expression. We hypothesize that PLZF protein levels are essential for the control of arNKT cell functions and if the levels are altered, the onset of obesity and metabolic disease will increase. Data supporting this conclusion will lead to future studies to determine if variability in PLZF expression in humans is potentially a contributing factor to obesity. Importantly, analysis of arNKT cells that do not function correctly is expected to reveal new information about the mechanisms by which arNKT cells normally function.