iNKT Cell Recognition of Endogenous Lipid Antigens

描述(申请人提供)：自然杀伤T细胞(INKT)已经进化到识别CD1d分子呈递的糖脂抗原。通过T细胞受体(TCR)刺激后，iNKT细胞反应非常迅速，这是先天反应而不是获得性反应的特征。INKT细胞参与调节与多种疾病相关的免疫反应，包括自身免疫、过敏、传染病和癌症。INKT细胞可通过两条主要途径被激活。微生物特异性CD1d限制性脂类可直接刺激iNKT细胞。或者，iNKT细胞可以通过识别CD1d限制性自身抗原和炎性细胞因子来激活。这表明iNKT细胞可能在对几乎所有感染性物质的反应中发挥作用。此外，iNKT细胞对自身的识别可能在癌症免疫中发挥重要作用，因为iNKT细胞在癌症、肉瘤和血液系统恶性肿瘤的免疫监测中发挥着关键作用。类似地，在缺血-再灌注损伤和镰状细胞疾病中触发的炎性级联似乎是iNKT细胞被自体脂质激活的直接结果。重要的是，能够触发iNKT细胞反应的自身抗原可能是这些细胞在发育过程中积极选择的原因。参与这些过程的自体脂质(S)的性质目前是一个有争议的话题。我们已经设计了iNKT T细胞受体，它保持了与“常规iNKT TCR”相同的特异性，但对抗原-CD1d复合体有更高的亲和力。使用这些独特的工具，我们已经开始识别当CD1d分子呈现时可以与TCR结合的自身抗原。通过独特和多管齐下的方法，我们建议研究iNKT细胞的自我配体是什么，以及它们是如何被识别的。最后，我们将使用一种高度创新的方法，评估这些新发现的自我配体如何影响iNKT细胞的发育。这些研究将确定优化iNKT细胞配体并最终调节iNKT细胞功能的指南，对基于糖脂的疫苗开发具有重要意义。

DESCRIPTION (provided by applicant): Natural Killer T (iNKT) cells have evolved to recognize glycolipid antigens presented by CD1d molecules. Following stimulation through their T cell receptor (TCR), iNKT cells respond very rapidly, as is characteristic of innate rather than adaptive responses. iNKT cells have been implicated in the regulation of immune responses associated with a broad range of diseases, including autoimmunity, allergy, infectious diseases and cancer. iNKT cells can be activated through two major pathways. Microbe-specific CD1d-restricted lipids can stimulate iNKT cells directly. Alternatively, iNKT cells can be activated via recognition of CD1d-restricted self-antigens, in combination with inflammatory cytokines. This suggests that iNKT cells might play a role in the response to nearly all infectious agents. Furthermore, recognition of "self" by iNKT cells might play an important role in cancer immunity as iNKT cells have been shown to play a critical role in the immune surveillance of carcinoma, sarcoma and hematopoietic malignancies. Similarly, the inflammatory cascade triggered during ischemia-reperfusion injury and sickle cell disease appears to be a direct consequence of iNKT cells activation by self-derived lipids. Importantly, self-antigens that can trigger an iNKT cell response may be responsible for the positive selection of these cells during their development. The nature of the self-lipid(s) that are involved in these processes is currently a subject of controversy. We have engineered iNKT T cell receptors that conserve the same specificity than "regular iNKT TCR" but have a higher affinity for the antigen-CD1d complex. Using these unique tools, we have started to identify self-antigens that can bind the TCR when presented by CD1d molecules. Through distinctive and multi-pronged approaches we propose to examine what is/are the self-ligands of iNKT cells and how they are recognized. Finally, we will assess, using a highly innovative approach, how these newly identified self-ligands affect iNKT cell development. These studies will define the guidelines to optimize iNKT cell ligands and ultimately regulate iNKT cell function, with important implications for glycolipid-based vaccine development.