T CELL RECOGNITION OF SELF LIPIDS PRESENTED BY CD1C

CD1蛋白（CD1a、CD1b、CD1c、CD1d）呈递脂质抗原，用于与T细胞抗原受体（TCR）特异性相互作用。这代表了导致T细胞活化的全新细胞途径，并显著扩大了T细胞识别的抗原范围。申请人的初步结果将CD 1c呈递抗原的第一个结构定义为甘露糖基磷酸多萜醇（MPD），这是存在于所有细胞生物体中的一类长链类异戊二烯脂质的成员。初步研究表明，TCR和CD1c介导人类T细胞对外源（分枝杆菌）和自身（人类）MPD的半合成类似物的应答，从而定义了α T细胞的脂质自身抗原。这种识别的三分子模型预测，CD1通过将脂质隔离在CD1的疏水沟内来呈递两亲性糖脂，导致抗原的碳水化合物部分呈递给TCR。拟议的研究将通过制备糖基化、饱和支化和脂质长度不同的类异戊二烯糖脂来测试该模型。将在等离子体共振、闪烁接近和基于细胞的测定中检测抗原类似物，以确定抗原结构在CD1c结合和T细胞活化的单独过程中的作用。特别是，类似物将被合成以定义将CD1c配体与由CD1b和CD1d呈递的配体区分开的结构，并确定将自身与外来MPD区分开的分子基础。我们提出了一种新的糖脂自身免疫模型，通过该模型，人类自身反应性T细胞识别与CD1c蛋白结合的自身类异戊二烯糖脂。这些研究将提供一个基本的了解的分子事件CD1c的脂质呈递给TCR和脂质自身抗原呈递的细胞基础。

CD1 proteins (CD1a, CD1b, CD1c, CD1d) present lipid antigens for specific interactions with the T cell antigen receptor (TCR). This represents a fundamentally new cellular pathway leading to T cell activation and significantly expands the range of antigens recognized by T cells. The applicant's preliminary results define the first structure of a CD1c-presented antigen to be mannosyl phosphodolichol (MPD), a member of a class of long chain isoprenoid lipids that are present in all cellular organisms. Preliminary studies indicated that the TCR and CD1c mediated human T cell responses to semi-synthetic analogs of both foreign (mycobacterial) and self (human) MPD, thus defining a lipid autoantigen for alphabeta T cells. A trimolecular model of this recognition predicts that CD1 presents amphipathic glycolipids by sequestering the lipid within the hydrophobic groove of CD1, resulting in presentation of the carbohydrate moiety of the antigen to the TCR. The proposed studies will test this model by preparing isoprenoid glycolipids that differ in glycosylation, saturation branching and length of the lipid. Antigen analogs will be tested in plasmon resonance, scintillation proximity and cell-based assays to determine the role of antigen structure in the separate processes of CD1c binding and T cell activation. In particular, analogs will e synthesize to define the structures that distinguish CD1c ligands from those presented by CD1b and CD1d and to determine the molecular basis of discrimination of self from foreign MPDs. We propose a new model of glycolipid autoimmunity by which human autoreactive T cells recognize self isoprenoid glycolipids bound to the CD1c protein. These studies will provide a basic understanding of the molecular events underlying CD1c-presentation of lipids to the TCR and the cellular basis of presentation of a lipid autoantigen.