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Analysis of Class II MHC and CD1d antigen presentation pathways in skin-derived d

皮肤源性d中II类MHC和CD1d抗原呈递途径分析

基本信息

批准号：
7365095
负责人：
ROBERT C FUHLBRIGGE
金额：
$ 20.86万
依托单位：
BRIGHAM AND WOMEN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-03-01 至 2012-02-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7365095
关键词：
Affect Animal Model Antigen Presentation Antigen Presentation Pathway Antigen Targeting Antigen-Presenting Cells Antigens Applications Grants Area B-Lymphocytes Biochemical Biological Bone Marrow CD1 Antigens CD1d antigen CD4 Positive T Lymphocytes Cathepsins Cell Line Cells Chimera organism Chimeric Proteins Class Coculture Techniques Complex Contact Sensitizing Agents Cross Presentation DNA Sequence Rearrangement Dendritic Cells Dermal Dermis Drug or chemical Tissue Distribution Early Endosome Endocytosis Endoplasmic Reticulum Endosomes Epidermis Equilibrium Exhibits Flow Cytometry Generations Genie Glycolipids Grant Green Fluorescent Proteins Guanine Nucleotide Dissociation Inhibitors Histocompatibility Antigens Class II Hour Human Hypersensitivity Immune Immune response Immune system Immunity Immunization In Situ Infection Infectious Agent Inflammation Inflammatory Interferon Type II Interleukin-4 Investigation Kinetics Knock-in Mouse Label Langerhans cell Learning Leukocytes Life Ligands Link Lipids Liquid substance Lymphoid Maintenance Major Histocompatibility Complex Measures Mediating Membrane Proteins Methodology Modeling Molecular Chaperones Monitor Mus Mutant Strains Mice Mutation Organ Pathway interactions Patients Peptides Peripheral Personal Satisfaction Phase Phenotype Population Principal Investigator Process Protein Isoforms Proteins Proteolysis Psoriasis Radio Reporting Research Personnel Resistance Role Route Secondary to Sentinel Skin Stimulus Surveys T-Cell Activation T-Lymphocyte Testing Tissues Transplantation Week antigen processing base bone cell type congenic cytokine design enhanced green fluorescent protein experience in vivo interstitial intracellular protein transport invariant chain irradiation keratinocyte lymph nodes migration monocyte mouse model pathogen prevent programs protein transport research study response segregation skin disorder trafficking transmission process uptake

项目摘要

DESCRIPTION (provided by applicant): Dendritic cells (DCs) are sentinels of the peripheral immune system that continuously survey their surroundings for pathogens, by fluid phase uptake and endocytosis. When pathogen-derived fragments are detected, DCs engulf the foreign material and in the process become activated. Engulfed proteins are processed and displayed as peptide/MHC complexes to Class II MHC-restricted T cells, while lipids are incorporated into CD1/(32m/lipid complexes for presentation to CD1-restricted T cells. Much of what is known about endosomal antigen processing, loading and presentation of Class II MHC molecules was learned through biochemical and cell biological analysis of B cell lines, and to a more limited extent, of cultured DCs. New methodology now makes it possible to visualize the uptake of red fluorescent antigen by live Class II MHC-positive DCs in situ in the epidermis of mice that express green fluorescent protein (GFP)-Class II MHC fusion proteins. Trafficking of antigen-experienced DCs to skin-draining lymph nodes can be tracked in live cells. First, we will study the protein and lipid antigen-presentation pathways in skin-derived DCs and lymph node-resident DCs. We will test our hypothesis that during inflammation, priming of immune responses in the skin requires cell-mediated transport of both protein and lipid antigens by epidermis- resident DCs (Langerhans cells) to skin-draining lymph nodes. Antigen presentation by DCs that reside in the T cell area of lymph nodes is essential for T cell priming. We hypothesize that antigen transfer from LC to a non-migratory lymph node-resident DCs is necessary for successful T cell priming to occur. Accordingly, mutant mice in which LCs express normal antigen endocytosis but defective endosomal processing should have limited phenotype. In contrast, mice expressing non-migratory DCs defective in endosomal processing should exhibit reduced T cell priming capacities. We will study antigen processing and Class II MHC presentation pathways in epidermis-derived Langerhans cells and lymph node-resident DC subtypes. Finally, we have succeeded to generate a new mouse model to study CD1-mediated antigen presentation in vivo. The possible involvement of CD1d to immune responses originating in the skin will be investigated in CD1d- yellow fluorescent protein knock-in mice.

描述（由申请人提供）：树突状细胞（DC）是外周免疫系统的哨兵，通过液相摄取和内吞作用不断地调查周围环境中的病原体。当检测到病原体衍生的片段时，树突状细胞会吞噬异物并在此过程中被激活。吞噬的蛋白质被加工并以肽/MHC复合物的形式展示给II类MHC限制性T细胞，而脂质则被整合到CD1/(32m/脂质复合物中以呈递给CD1限制性T细胞。关于内体抗原加工、II类MHC分子的装载和呈递的大部分知识是通过B细胞系的生化和细胞生物学分析得知的，以及在更有限的范围内培养的 DC。现在，新的方法可以使表达绿色荧光蛋白 (GFP)-II 类 MHC 融合蛋白的小鼠表皮中的活 II 类 MHC 阳性 DC 对红色荧光抗原的摄取进行可视化。可以追踪经历过抗原的 DC 向皮肤引流淋巴结的贩运活细胞。首先，我们将研究皮肤源性 DC 和淋巴结驻留 DC 中的蛋白质和脂质抗原呈递途径。我们将检验我们的假设，即在炎症期间，皮肤免疫反应的启动需要表皮驻留 DC（朗格汉斯细胞）通过细胞介导的方式将蛋白质和脂质抗原转运至皮肤引流淋巴结。位于淋巴结 T 细胞区域的 DC 呈递抗原对于 T 细胞启动至关重要。我们假设抗原从 LC 转移到非迁移性淋巴结驻留 DC 是 T 细胞成功启动所必需的。因此，LC表达正常抗原内吞作用但内体加工有缺陷的突变小鼠应具有有限的表型。相比之下，小鼠表达内体加工缺陷的非迁移 DC 应该表现出 T 细胞启动能力降低。我们将研究表皮衍生朗格汉斯细胞和淋巴结驻留 DC 亚型中的抗原加工和 II 类 MHC 呈递途径。最后，我们成功地建立了一种新的小鼠模型来研究 CD1 介导的体内抗原呈递。 CD1d 可能参与将在 CD1d-黄色荧光蛋白敲入小鼠中研究对源自皮肤的免疫反应的影响。