Structural determinants of CD1d-restricted TCR function

描述(由申请人提供)：CD1d限制性T细胞(或“NKT”细胞)识别脂质和甘油三脂抗原，并具有影响各种免疫过程的功能。它们可以促进Th1反应，介导肿瘤排斥反应和对各种微生物感染的防御，而且它们似乎在预防自身免疫性疾病方面也发挥着重要作用。目前尚不清楚这些不同的功能是如何调控的，但一个重要的特征可能是抗原刺激的性质。NKT细胞遇到的TCR信号的强度可能会严重影响所引发的功能反应的类型，不同的抗原在信号强度上可能会有所不同。例如，给予合成糖脂(-GaICer)可强烈刺激CD1d受限的T细胞，导致Th1和Th2细胞因子的有效分泌，以及其他效应器功能。相反，识别自身抗原会产生较弱的反应，在没有炎性共刺激的情况下，这可能会导致NKT细胞功能增强，从而促进外周耐受。这些研究将调查CD1d限制性T细胞的TCR结构如何决定抗原识别和反应能力。该方法利用了CD1d限制性T细胞克隆，这些克隆具有新的“非常规”TCR，并且在区分两种密切相关的脂类方面不同于V(24-不变T细胞)。这些特殊的CD1d限制性T细胞提供了一个独特的机会，将TCR结构与脂类抗原的功能识别联系起来。其具体目的是：1)研究CD1d限制性T细胞对不同脂类的反应和TCR序列的关系；2)鉴定和测试决定抗原和CD1d识别的TCR结构特征；3)研究T细胞对不同脂类抗原的反应与TCR对抗原的亲和力、免疫突触形成和TCR信号转导的关系。这些目标的完成将使我们更好地了解NKT细胞的抗原特异性是如何确定的，以及不同抗原的识别如何与功能激活有关。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，对于开发它们的各种功能用于诸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以及增强外周耐受机制以对抗自身免疫性疾病的能力至关重要。

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.