Th1/Th2 Glycolipid Adjuvants

自然杀伤T细胞(NKT细胞)在调节免疫反应中起着重要作用。NKT细胞是 由CD1d提出的糖脂抗原刺激，在过去的几年中取得了重大进展 在理解这一过程方面取得了进展。NKT细胞的天然抗原已被鉴定，并结晶 糖脂结合的CD1d的结构已经被解决。由于导致NKT细胞刺激的因素有 已阐明，糖脂运输和与T细胞受体(TCR)的特异性相互作用的重要性是 正在浮现。然而，糖脂的贩运以及与TCRs的相互作用还不是很清楚。建议 研究包括开发用于研究特定贩运事件的标记糖脂； 具体地说，糖脂的结构变化对贩运的影响以及如何在 运输影响NKT细胞释放细胞因子的Th1/Th2偏向。糖脂和CD1d的研究 与TCR的相互作用将涉及已知抗原的递增结构修改，以确定 联想和刺激的要求。此外，已经鉴定出糖脂功能可以 在不对NKT细胞刺激产生负面影响的情况下进行修改，该信息提供了一种 利用附着在糖脂上的小分子修饰TCR对糖脂-CD1d复合体的亲和力。 预计更高的亲和力将导致NKT细胞的长期刺激和细胞因子的增加 然而，这种亲和力对细胞因子释放谱的影响尚不清楚，这些研究将 提供这些信息。已知的为NKT细胞产生天然抗原的微生物数量相当 与已知能直接刺激NKT细胞的小细菌和相关细菌将被筛选出NKT刺激 行为。然后将通过全合成来确定和确认抗原的结构。 与公共健康相关：NKT细胞的反应影响感染、肿瘤等疾病状态 排斥反应和自身免疫性疾病。了解糖脂如何刺激不同的反应 NKT细胞将促进利用这些反应来改善人类健康。拟议的研究将增加 这一认识同时增加了刺激NKT细胞的糖脂的武器库。

Natural killer T cells (NKT cells) play an important role in regulating immune responses. NKT cells are stimulate by glycolipid antigens presented by CD1d, and in the last few years significant advances have been made in understanding this process. Natural antigens for NKT cells have been identified, and crystal structures of CD1d bound to glycolipids have been solved. As factors leading to NKT cell stimulation are elucidated, the importance of glycolipid trafficking and specific interactions with T cell receptors (TCRs) is emerging. However, glycolipid trafficking and interactions with TCRs are not well understood. Proposed research includes development of labeled glycolipids for use in studying specific trafficking events; specifically, the influences of structural variations of glycolipids on trafficking and how differences in trafficking influence the Th1/Th2 bias of cytokine release by NKT cells. Studies of glycolipid and CD1d interactions with TCRs will involve incremental structural modifications of known antigens to determine requirements for association and stimulation. In addition, glycolipid functionality has bee identified that can be modified without impacting negatively NKT cell stimulation, and this information provides a means of using small molecules appended to glycolipids to modify the affinity of TCRs for glycolipid-CD1d complexes. It is anticipated that higher affinity will result in prolonged stimulation of NKT cells and increased cytokine release; however, the impact of this affinity on cytokine release profiles is not known and these studies will provide that information. The number of known organisms producing natural antigens for NKT cells is rather small, and bacteria related to those know to stimulate NKT cell directly will be screened for NKT stimulatory behavior. Structures of antigens will then be determined and confirmed through total synthesis. Relevance to Public Health: Responses of NKT cells influence disease states including infection, tumor rejection, and autoimmune diseases. An understanding of how glycolipids stimulate different responses from NKT cells will facilitate use of these responses to improve human health. Proposed research will increase this understanding while augmenting the arsenal of glycolipids that stimulate NKT cells.