Structural Immunology of CD1 and CD1-TCR Complexes

描述（由申请人提供）：在过去的10年中，积累了大量的数据，这些数据证明了糖脂反应性T细胞在自身免疫性疾病、宿主防御和肿瘤发展中的作用。T细胞和NKT细胞可以对由CD1分子呈递的自身和外源抗原的广泛库做出反应，并且可以通过细胞毒性T淋巴细胞（CTL）触发对抗原呈递细胞的杀伤，或者通过产生可溶性抗体从体液免疫系统募集帮助（T辅助细胞）。我们的实验室对细胞免疫中脂质抗原识别的分子机制感兴趣。为了实现这一目标，我们通过表面等离子体共振研究（SPR）确定各种糖脂反应性T细胞受体（TCR）与各种CD 1抗原呈递分子的结合动力学。我们将进一步将获得的结果与通过使用T细胞杂交瘤测量T细胞活化后细胞因子产生获得的数据相关联。最终，我们建议通过X射线晶体学确定与不同脂质和同源T细胞受体（TCR）复合的CD1抗原受体的三维结构。我们具体解决以下具体目标：1）人类和小鼠硫酸酯反应性NKT细胞的生物化学和功能特性是什么。我们将确定硫苷脂负载的人CD1a和小鼠CD1d与各自的TCR复合的结构，并通过SPR表征其结合动力学。这两种复合物的比较将提供洞察的相似性和差异的硫苷脂识别的免疫系统，并将阐明其激活的分子机制。2)我们将在结构和功能上表征糖脂识别伯氏疏螺旋体糖脂的人和小鼠NKT细胞的差异。3)我们将表征新型内源性自身脂质与小鼠CD1d的结合及其被NKT细胞识别。对自身与微生物抗原呈递差异的结构见解将有助于理解微生物脂质和脂质反应性T细胞在宿主防御和自身免疫性疾病中的作用。公共卫生相关性：NKT细胞是特化的淋巴细胞，其由几种亚型组成，并且可以在自身免疫性疾病如多发性硬化症的过程中对来自感染性生物体（如莱姆病的病原体伯氏疏螺旋体）的糖脂和自身脂质产生应答。在分子水平上了解这些细胞类型的功能特性对于未来开发新的化疗药物或佐剂以对抗这两种疾病至关重要。

DESCRIPTION (provided by applicant): Over the past 10 years, a tremendous amount of data has accumulated, which demonstrates the role of glycolipid-reactive T cells in autoimmune disease, host defense and tumor development. T cells and NKT cells can respond to a broad pool of self and foreign antigens presented by CD1 molecules and can trigger killing of the antigen presenting cell, through cytotoxic T lymphocytes (CTLs), or recruit help (T helper cells) from the humoral immune system through production of soluble antibodies. Our lab is interested in the molecular mechanisms of lipid antigen recognition in cell-mediated immunity. Toward this goal, we determine the binding kinetics of various glycolipid- reactive T cell receptor's (TCR's) with various CD1 antigen-presenting molecules by surface plasmon resonance studies (SPR). We will further correlate the obtained results with data obtained by measuring cytokine production upon T cell activation using T cell hybridomas. Ultimately we propose to determine the three-dimensional structure of CD1 antigen receptors in complex with different lipids and cognate T cell receptors (TCR's) by x-ray crystallography. We specifically address the following specific aims: 1) What are the biochemical and functional properties of human and mouse sulfatide-reactive NKT cells. We will determine the structure of sulfatide loaded human CD1a and mouse CD1d in complex with the respective TCR and characterize their binding kinetics by SPR. Comparisons of both complexes will provide insights into the similarities and disparities of sulfatide recognition by the immune system and will shed light on the molecular mechanism of their activation. 2) We will structurally and functionally characterize differences in glycolipid recognition of Borrelia burgdorferi glycolipids by human and mouse NKT cells. 3) We will characterize binding of novel endogenous self-lipids to mouse CD1d and their recognition by NKT cells. Structural insights into the differences of self vs. microbial antigen presentation will help understand the role of microbial lipids and lipid-reactive T cells in host defense and autoimmune diseases. Public Health Relevance: NKT cells are specialized lymphocytes that consist of several subtypes and can respond to glycolipids from infectious organisms, such as Borrelia burgdorferi the causative agent of Lyme disease and self-lipids, during the course of autoimmune disease such as Multiple sclerosis. Understanding the functional properties of these cell types at a molecular level is crucial for the future development of novel chemotherapeutic agents or adjuvants to combat both diseases.