Structural determinants of CD1d-restricted TCR function

描述（由申请人提供）：CD 1d限制性T细胞（或“NKT”细胞）识别脂质和糖脂抗原，并具有可影响多种免疫过程的功能。它们可以促进Th 1应答，介导肿瘤排斥和防御各种微生物感染，并且它们似乎在预防自身免疫性疾病中发挥重要作用。这些截然不同的功能是如何调节的尚不清楚，但一个重要的特征可能是抗原刺激的性质。NKT细胞所遇到的TCR信号的强度可能严重影响所引发的功能性应答的类型，并且不同的抗原可能在信号强度上有所不同。例如，施用合成糖脂（-GaICer）有力地刺激CD 1d限制性T细胞，导致Th 1和Th 2细胞因子的快速有效分泌以及其他效应子功能。相比之下，自身抗原的识别产生较弱的反应，这在不存在炎性共刺激的情况下可能导致促进外周耐受的NKT细胞功能。这些研究将探讨CD 1d限制性T细胞的TCR结构如何决定抗原识别和反应性。该方法利用具有新的“非经典”TCR的CD 1d限制性T细胞克隆，并且在区分两种密切相关的脂质方面不同于V β 24不变T细胞。这些特殊的CD 1d限制性T细胞提供了将TCR结构与脂质抗原的功能识别相关联的独特机会。具体目标是：i）研究CD 1d限制性T细胞对不同脂质的应答与TCR序列之间的关系; ii）鉴定并测试决定抗原和CD 1d识别的TCR结构特征; iii）研究T细胞对不同脂质抗原的应答如何与TCR对抗原的亲和力、免疫突触形成和TCR信号转导相关。这些目标的完成将提供一个更好的理解如何确定NKT细胞的抗原特异性，以及如何识别不同的抗原与功能激活。了解如何刺激这些多方面的T细胞以实现特定的所需反应将是至关重要的能力，以利用其不同的功能，例如在生物恐怖袭击事件中提供短期免疫刺激，促进有效的抗肿瘤反应，并增强外周耐受机制以对抗自身免疫性疾病。

DESCRIPTION (provided by applicant): CD1d-restricted T cells (or "NKT" cells) recognize lipid and gtycolipid antigens, and have functions that can impact a variety of immunological processes. They can contribute to Th1 responses that mediate tumor rejection and defense against a variety of microbial infections, and they also appear to play an important role in preventing autoimmune disease. How these contrasting functions are regulated remains unclear, but an important feature is likely to be the nature of the antigenic stimulus. The strength of the TCR signal encountered by an NKT cell may critically affect the type of functional response that is elicited, and different antigens may vary in signalling strength. For example, administration of the synthetic glycolipid (-GaICer powerfully stimulates CD1d-restricted T cells, resulting rapidly in potent secretion of both Th1 and Th2 cytokines, and other effector functions. In contrast, recognition of self antigens produces weaker responses, which in the absence of inflammatory co-stimulation may result in NKT cell functions that promote peripheral tolerance. These studies will investigate how the TCR structure of CD1d-restricted T cells determines antigen recognition and reactivity. The approach utilizes CD1d-restricted T cell clones that have novel "non-cannonical" TCRs, and which differ from V(24-invariant T cells in distinguishing between two closely related lipids. These exceptional CD1d-restricted T cells provide a unique opportunity to correlate TCR structure with functional recognition of lipid antigens. The specific aims are : i) investigate the relationship between CD1d-restricted T cells responses to different lipids and TCR sequence; ii) identify and test TCR structural features that determine antigen and CD1d recognition; iii) investigate how T cell responses to different lipid antigens relate to TCR affinity for the antigen, immunological synapse formation, and TCR signal transduction. Completion of these aims will provide a better understanding of how the antigen specificity of NKT cells is determined, and how recognition of different antigens relates to functional activation. Understanding how to stimulate these multi-faceted T cells to achieve specifically the desired response will be critical to the ability to exploit their varied functions for uses such as providing short-term immunostimulation in the event of a bio-terrorist attack, promoting effective anti-tumor responses, and enhancing peripheral tolerance mechanisms to combat autoimmune disease.