Binding and Presentation of Lipid Antigens by CD1

描述（由申请人提供）：被称为1型或不变NKT细胞（iNKT细胞）的T淋巴细胞识别CD1d蛋白呈递的特异性脂质配体，并且这一cd1依赖性免疫反应的组成部分在人和小鼠之间高度保守。在小鼠模型中进行的许多详细研究表明，iNKT细胞有助于对抗病原体的免疫应答，消除恶性肿瘤，维持免疫耐受和预防自身免疫性疾病。近年来，由于鉴定出了多种形式的可特异性激活iNKT细胞的合成a-半乳糖神经酰胺（aGalCer），在理解和潜在利用iNKT细胞的许多免疫活性方面取得了巨大进展。目前的建议集中在鉴定修饰形式的aGalCer，当用于刺激小鼠或人iNKT细胞时，可以激活不同的细胞因子模式。在我们正在进行的研究中，已经确定了许多th2细胞因子偏态形式的aGalCer，我们提出了新的合成方法来创造更多的aGalCer类似物，包括基于细胞因子产生或其他作用具有耐受性或促炎活性的例子。这些化合物将使用分析系统来分析小鼠和人类iNKT细胞反应，以确定那些最适合进行转化研究的化合物。利用CD1d/aGalCer复合物和可溶性iNKT细胞抗原受体特异性的新型单克隆抗体试剂，我们将开展一系列研究，以确定各种aGalCer类似物刺激细胞因子显著不同模式的机制。还提出了在疫苗接种模型系统中优化选定的aGalCer类似物的佐剂特性的研究。这些研究将增加我们对iNKT细胞许多潜在活性调控机制的理解，并将有助于开发这种T细胞亚群的糖脂激活剂的治疗应用。

DESCRIPTION (provided by applicant): T lymphocytes known as type 1 or invariant NKT cells (iNKT cells) recognize specific lipid ligands presented by the CD1d protein, and this component of the CD1-dependent immune response is highly conserved between humans and mice. Many detailed studies in mouse models have shown that iNKT cells contribute to immune responses against pathogens, elimination of malignant tumors, maintenance of immunological tolerance and prevention of autoimmune diseases. Great progress in understanding and potentially harnessing the many immunological activities of iNKT cells has been made in recent years as a result of the identification of various forms of synthetic a-galactosylceramide (aGalCer) that specifically activate these cells. The current proposal is focused on the identification of modified forms of aGalCer that activate different cytokine patterns when used to stimulate mouse or human iNKT cells. Numerous Th2-cytokine biasing forms of aGalCer have been identified in our ongoing studies, and we propose new synthetic approaches to create additional aGalCer analogues that will include examples with tolerogenic or proinflammatory activities based on cytokine production or other effects. These compounds will be characterized in detail using assay systems to analyze both mouse and human iNKT cell responses to identify those that are most suitable to carry forward into translational studies. Using new monoclonal antibody reagents specific for CD1d/aGalCer complexes, and soluble iNKT cell antigen receptors, we will carry out a range of studies to determine the mechanisms that lead to the stimulation of markedly different patterns of cytokines by various aGalCer analogues. Studies to optimize the adjuvant properties of selected aGalCer analogues in model systems of vaccination are also proposed. These studies will increase our understanding of the mechanisms governing the regulation of the many potential activities of iNKT cells, and will contribute to development of therapeutic applications for glycolipid activators of this T cell subset.