Structural Immunology of CD1 and CD1-TCR Complexes

在过去的10年里，积累了大量的数据，其中 说明糖脂反应性T细胞在自身免疫性疾病、宿主防御中的作用 和肿瘤的发展。T细胞和NKT细胞可以对广泛的自我和 由CD1分子呈递的外来抗原，可触发对该抗原的杀伤 提供细胞，通过细胞毒性T淋巴细胞(CTL)，或招募帮助(T辅助细胞) 从体液免疫系统通过产生可溶性抗体。我们的实验室是 对细胞介导的脂类抗原识别的分子机制感兴趣 豁免权。为此，我们测定了各种糖脂反应的结合动力学。 T细胞受体S与多种CD_1抗原提呈分子的相互作用 表面等离子体共振研究(SPR)。我们将进一步将所获得的结果相互关联。 通过使用T细胞测量T细胞激活时细胞因子的产生而获得的数据 杂交瘤。最终，我们建议确定CD1的三维结构 不同脂类与同源T细胞受体复合体中的抗原受体(TCR？S) X射线结晶学。我们具体解决以下具体目标：1)什么是 人和小鼠硫脂反应性NKT的生化和功能特性 细胞。我们将确定硫脂负载的人CD1a和小鼠CD1d的结构 与各自的TCR形成络合物，并用SPR表征其结合动力学。 对这两个复合体的比较将使我们深入了解它们的相似和不同之处 通过免疫系统识别硫脂，并将阐明分子 它们的激活机制。2)我们将在结构和功能上表征 人和人对伯氏疏螺旋体糖脂识别的差异 小鼠NKT细胞。3)我们将表征新型内源性自体脂质与 小鼠CD1d及其对NKT细胞的识别作用对差异的结构性洞察 自身与微生物抗原提呈的对比将有助于理解微生物脂类的作用 以及宿主防御和自身免疫性疾病中的脂质反应性T细胞。

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 glycolipidreactive 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 disparieties 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.