Binding and Presentation of Lipid Antigens by CD1

描述(由申请人提供)：T淋巴细胞被称为1型或不变NKT细胞(iNKT细胞)识别CD1d蛋白呈现的特定脂类配体，并且CD1依赖的免疫反应的这一组成部分在人类和小鼠之间高度保守。在小鼠模型中的许多详细研究表明，iNKT细胞有助于对抗病原体的免疫反应、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，由于鉴定了多种形式的合成α-半乳糖基神经酰胺(AGalCer)来特异性激活iNKT细胞，在理解和潜在利用iNKT细胞的许多免疫学活性方面取得了很大进展。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类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，已经发现了许多Th2细胞因子偏置形式的aGalCer，我们提出了新的合成方法来创建更多的aGalCer类似物，其中将包括基于细胞因子产生或其他影响而具有耐受或促炎活性的例子。这些化合物将使用测试系统进行详细表征，以分析小鼠和人类iNKT细胞的反应，以确定最适合进行翻译研究的化合物。利用针对CD1d/aGalCer复合体的新的单抗试剂和可溶性的iNKT细胞抗原受体，我们将开展一系列研究，以确定各种aGalCer类似物刺激明显不同模式的细胞因子的机制。还提出了在疫苗接种模型系统中优化选定的aGalCer类似物佐剂性能的研究。这些研究将增加我们对调节iNKT细胞许多潜在活性的机制的理解，并将有助于开发这一T细胞亚群的糖脂激活剂的治疗应用。与公共卫生相关：该项目将开发专门激活T淋巴细胞的一种特殊亚群的化合物，称为iNKT细胞。这些T细胞有能力刺激或抑制免疫反应，这取决于它们被激活的方式。这项提案中提出的研究将确定选择性激活iNKT细胞的刺激或抑制功能的化合物，这将导致能够更精确地控制这些细胞的功能，以预防或治疗人类疾病。INKT细胞激活剂的潜在应用范围非常广泛，包括将它们用作预防1型糖尿病或多发性硬化症等自身免疫性疾病的药物，以及将它们纳入感染和癌症的新疫苗。

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. PUBLIC HEALTH RELEVANCE: This project will develop chemical compounds that specifically activate a specialized subset of T lymphocytes known as iNKT cells. These T cells have the ability to either stimulate or suppress immune responses, depending on how they are activated. The studies put forth in this proposal will identify compounds that selectively activate either the stimulatory or suppressive functions of iNKT cells, which will lead to the ability to more precisely control the functions of these cells for the prevention or treatment of human disease. The potential range of applications for iNKT cell activators is very broad and includes their use as drugs for prevention of autoimmune diseases such as type 1 diabetes or multiple sclerosis, as well as their incorporation into new vaccines for infections and cancer.