T CELL RECOGNITION OF SELF LIPIDS PRESENTED BY CD1C

CD1 蛋白（CD1a、CD1b、CD1c、CD1d）呈递脂质抗原，与 T 细胞抗原受体 (TCR) 发生特异性相互作用。这代表了一种导致 T 细胞激活的全新细胞途径，并显着扩大了 T 细胞识别的抗原范围。申请人的初步结果将CD1c呈递的抗原的第一个结构定义为甘露糖基磷酸多酚(MPD)，它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 的半合成类似物做出反应，从而定义了 Alphata 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，从而将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。抗原类似物将在等离子体共振、闪烁邻近和基于细胞的测定中进行测试，以确定抗原结构在 CD1c 结合和 T 细胞激活的单独过程中的作用。特别是，将合成类似物来定义将 CD1c 配体与 CD1b 和 CD1d 所呈现的配体区分开来的结构，并确定区分自身与外来 MPD 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。这些研究将提供对 CD1c 向 TCR 呈递脂质的分子事件以及呈递脂质自身抗原的细胞基础的基本了解。

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.