CD1 presentation of self glycolipids and lipopeptides to T cells

CD1 将自身糖脂和脂肽呈递给 T 细胞

• 批准号: 8655786
• 负责人: DAVID Branch MOODY
• 金额: $ 36.11万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-09-20 至 2017-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8655786
• 关键词: Affect; Amino Acids; Animal Model; Antigens; Autoantigens; Autoimmune Diseases; Autoimmune Process; Autoimmunity; Binding; Biology; Brain; CD1 Antigens; Cells; Colon; Complex; Data Set; Dendritic Cells; Development; Diabetes Mellitus; Diagnostic tests; Gene Deletion; Glycolipids; Grant; High Pressure Liquid Chromatography; Home environment; Homeostasis; Human; Immune; Immune response; Individual; Joints; Knowledge; Langerhans cell; Lead; Ligands; Lipid Binding; Lipids; Liquid Chromatography; Lung; Mass Spectrum Analysis; Measures; Mediating; Molecular; Molecular Structure; Molecular Target; Multiple Sclerosis; Mus; National Institute of Arthritis and Musculoskeletal and Skin Diseases; Nature; Organ; Organ Model; Pancreas; Pathway interactions; Patients; Pattern; Peptide/MHC Complex; Peptides; Play; Proteins; Psoriasis; Research; Rheumatoid Arthritis; Role; Self Perception; Skin; Structure; Syndrome; System; T cell response; T-Cell Activation; T-Cell Receptor; T-Lymphocyte; Testing; Thyroid Gland; Thyroiditis; Tissues; To autoantigen; Work; autoreactive T cell; autoreactivity; base; biliary tract; cell type; chemical property; cytokine; density; human tissue; in vivo; interleukin-22; microsomal triglyceride transfer protein; mouse model; research study; tool

DESCRIPTION (provided by applicant): CD1 presentation of self glycolipids and lipopeptides to T cells T cells that recognize autoantigens play a central role in psoriasis, thyroiditis, diabetes, multiple sclerosis, rheumatoid arthritis and other human autoimmune diseases. For many years all autoantigens for T cells were thought to be peptides bound to MHC proteins. However, new evidence shows that cellular lipids activated T cells when bound to CD1 proteins expressed on Langerhans cells and other dendritic cells. Recent studies show that CD1 and lipid autoreactive T cells occur frequently in individuals, such that they can now be considered a normal part of human immune responses. In particular, CD1a activates T cells that make IL-22, a cytokine that contributes to psoriasis. Whereas nearly all prior study of T cell autoantigens have focused on peptides, these findings considerably broaden the spectrum of autoantigens to include a variety of cellular lipids. Discovery of CD1 autoreactive T cells opens up a new and general pathway for discovering autoantigens that contribute to autoimmune disease and the use of lipids to treat autoimmune diseases. Whereas mouse models provide important information about in vivo function, tissue antigens and CD1-mediated T cell responses differ between mouse and human systems. Therefore, this proposal uses human tissues from normal donors and autoimmune disease patients to isolate new antigens and new T cell types. Specifically, experiments will use mass spectrometry to broadly measure the mass and chemical properties of lipids bound to human CD1a, CD1b and CD1c proteins. From this large pool of candidate autoantigens, lipids that lead to the strongest T cell activation will be identifed using T cell clones and polyclonal T cells from patients. After isolating antigenic compounds from tissues by liquid chromatography, their molecular structures will be solved by mass spectrometry. CD1 proteins and antigens will be used to measure T cell responses in normal donors and patients to test new general hypotheses about the role of CD1 and interleukin-22 in skin and thyroid autoimmunity.

描述（由申请人提供）：自身糖脂和脂肽向T细胞的CD 1呈递识别自身抗原的T细胞在银屑病、甲状腺炎、糖尿病、多发性硬化症、类风湿性关节炎和其它人类自身免疫性疾病中起中心作用。多年来，所有T细胞的自身抗原都被认为是与MHC蛋白结合的肽。然而，新的证据表明，当细胞脂质与朗格汉斯细胞和其他树突状细胞上表达的CD 1蛋白结合时，T细胞被激活。最近的研究表明，CD 1和脂质自身反应性T细胞在个体中频繁发生，因此它们现在可以被认为是人类免疫反应的正常部分。特别是，CD 1a激活T细胞，使IL-22，一种细胞因子，有助于银屑病。尽管几乎所有先前的T细胞自身抗原研究都集中在肽上，但这些发现大大拓宽了自身抗原的范围，包括各种细胞脂质。CD 1自身反应性T细胞的发现为发现导致自身免疫性疾病的自身抗原和使用脂质治疗自身免疫性疾病开辟了一条新的通用途径。尽管小鼠模型提供了有关体内功能的重要信息，但小鼠和人类系统之间的组织抗原和CD 1介导的T细胞反应有所不同。因此，该提案使用来自正常供体和自身免疫性疾病患者的人体组织来分离新的抗原和新的T细胞类型。具体而言，实验将使用质谱法广泛测量与人CD 1a、CD 1b和CD 1c蛋白结合的脂质的质量和化学性质。从这个大的候选自身抗原库中，将使用来自患者的T细胞克隆和多克隆T细胞来鉴定导致最强T细胞活化的脂质。在通过液相色谱法从组织中分离抗原化合物之后，将通过质谱法解析其分子结构。CD 1蛋白和抗原将用于测量正常供体和患者的T细胞反应，以测试关于CD 1和白细胞介素-22在皮肤和甲状腺自身免疫中的作用的新的一般假设。