Molecular studies of lipid presentation and T cell recognition of CD1c

CD1c 脂质呈递和 T 细胞识别的分子研究

• 批准号: 8658193
• 负责人: Erin June Adams
• 金额: $ 36.61万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-05-15 至 2014-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8658193
• 关键词: Address; Affect; Antigens; Binding; Biochemical; CD1 Antigens; Cell Wall; Cell surface; Cells; Characteristics; Collaborations; Complex; Crystallization; Crystallography; Data; Disease; Engineering; Family; Genus Mycobacterium; Health; Homologous Gene; Human; Hydrocarbons; Immune; Immune response; Immunity; In Vitro; Individual; Interferons; Knowledge; Lead; Libraries; Ligands; Light; Lipid Binding; Lipids; Major Histocompatibility Complex; Memory; Modeling; Modification; Molecular; Molecular Chaperones; Mus; Mycobacterium tuberculosis; Natural Killer Cells; Nature; Peptides; Play; Population; Process; Protein Family; Proteins; Randomized; Role; Saposins; Structure; Sulfoglycosphingolipids; T-Lymphocyte; Tail; Tuberculosis; Variant; Work; base; cytokine; cytotoxicity; direct application; falls; infancy; insight; killer T cell; lipid structure; lipid transfer protein; member; molecular recognition; mouse model; novel; pathogen; peripheral blood; receptor; vaccine development

DESCRIPTION (provided by applicant): CD1c is a member of the CD1 family of proteins that are similar in structure to Major Histocompatibility Complex class I molecules. CD1 molecules have evolved unique lipid binding pockets (called A' and F') ideally suited for binding diverse lipid antigens via their hydrophobic hydrocarbon tails. CD1c falls into the Group 1 family of CD1 molecules found in humans; homologues are lacking in the mouse. Because we lack a tractable model by which to probe the function of Group 1 CD1 molecules, little is known about the immunological function of CD1c and the ¿¿ T cells that recognize it. Our recent crystal structure of CD1c shed light on this topic, revealing several unique features of this molecule that endows it with the capacity to bind diverse antigens. This structure also showed how CD1c presents a cell-wall lipid of Mycobacterium tuberculosis (MPM), a key potential target for vaccine development, and provides clues as to how a dodecameric N- terminally acylated lipopeptide ("lipo12") can also be presented. However, it is still unknown how CD1c presents other lipids, how this complex is recognized by ¿¿ T cells, and what characteristics dictate the ¿¿ T cell repertoire specific for CD1c (and whether this changes with different lipid antigens). In order to address these questions and more fully understand CD1c and its role in presenting diverse lipids to ¿¿ T cells, we will use the following strategies: our first aim, "To characterize the biophysical and structural details of CD1c lipid presentation." is focused on understanding the structural features of CD1c presentation and how intrinsic (lipid structure) and extrinsic (pH and chaperones) factors modulate CD1c's lipid repertoire. Our second aim, "To define how ¿¿ TCRs recognize CD1c/lipid ligands at the molecular level." is focused on using structural, biophysical and functional approaches to reveal how ¿¿ TCRs recognize CD1c/lipid at the molecular level. This is a key question relevant to globally understanding T cell recognition: How do diverse ¿¿ T cells "see" CD1 molecules? Is this recognition like classical ¿¿ TCR/MHC-like? Or are there features reminiscent of invariant Natural Killer T cell recognition of CD1d? Currently we have no information on this process. Finally, our third aim, "To characterize the repertoire of ¿¿ T cells that recognize CD1c." will focus on identifying the ¿¿ T cell repertoire that is CD1c responsive and to characterize these T cells for cell-surface markers (co-receptors, memory markers), effector functions (cytokine secretion and/or cytotoxicity) and the sequence of their TCRs, specifically to determine whether there are motifs in the CDR loops that are used in this recognition process. We will explore the human repertoire from health and diseased individuals and will make use of a humanized CD1c murine model to explore the T cell repertoire there. Currently our understanding of CD1c's contribution to human immunity is in its infancy, yet hints at its importance in pathogen recognition (such as M. tuberculosis) are already evident. Our proposal will expand our understanding of CD1c lipid presentation and the T cells that are reactive to it.

描述（由适用提供）：CD1C是CD1蛋白质家族的成员，其结构与主要的组织相容性复合物I类分子相似。 CD1分子已经进化出独特的脂质结合口袋（称为A和F'），非常适合通过其疏水烃尾巴结合潜水员脂质抗原。 CD1C落入人类发现的CD1分子的第一组家族。小鼠缺乏同源物。因为我们缺乏可探测1组CD1分子功能的可进行的模型，所以对识别它的CD1C和«t细胞的免疫功能知之甚少。我们最近的CD1C晶体结构阐明了该主题，揭示了该分子的几个独特特征，该特征赋予其结合发散抗原的能力。该结构还显示了CD1C如何呈现结核分枝杆菌（MPM）的细胞壁脂质，这是疫苗发育的关键潜在潜在靶标，并提供有关如何呈现公约N-终末酰化脂蛋白（“ Lipo12”）的线索。但是，CD1C如何呈现其他脂质，如何通过„ T细胞识别该复合物以及哪些特征决定了CD1C特有的特定的特征（以及这是否会随着不同的脂质抗原的变化）。为了解决这些问题，并更充分理解CD1C及其在向潜水脂质展示向T细胞中的作用，我们将使用以下策略：我们的第一个目的：“表征CD1C脂质呈现的生物物理和结构细节”。专注于理解CD1C表示的结构特征，以及内在的（脂质结构）和外部（pH和伴侣）因子如何调节CD1C的脂质库。我们的第二个目的是“定义»tcrs如何在分子水平识别CD1C/脂质配体”。专注于使用结构，生物物理和功能性方法来揭示ooclecular水平上的CD1C/脂质如何识别。这是与全球理解T细胞识别相关的关键问题：潜水员如何“见” CD1分子？这种识别是否像古典„„ TCR/MHC一样？还是有使人想起CD1D不变的天然杀伤细胞识别的特征？目前，我们没有有关此过程的信息。最后，我们的第三个目标是“表征识别CD1C的T细胞的曲目”。将专注于识别CD1C反应性的T细胞库，并表征这些T细胞的细胞表面标记（共受体，记忆标记），效应子功能（细胞因子分泌和/或细胞毒性）及其TCR的序列，特别是确定在CDR上使用的基序。我们将探索健康和失职的人的人类曲目，并将利用人性化的CD1C鼠模型来探索那里的T细胞曲目。目前，我们对CD1C对人免疫学的贡献的理解尚处于起步阶段，但暗示其在病原体识别（例如结核分枝杆菌）中的重要性已经是证据。我们的建议将扩展我们对CD1C脂质表现的理解以及对其反应的T细胞。