Characterization of the MHC Class II Peptide Loading Complex

MHC II 类肽装载复合物的表征

• 批准号: 8383558
• 负责人: James R Drake
• 金额: $ 23.7万
• 依托单位: ALBANY MEDICAL COLLEGE
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-08-01 至 2014-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8383558
• 关键词: Antigen Presentation Pathway; Antigen-Presenting Cells; Antigens; Autoimmunity; Automobile Driving; B-Cell Receptor Binding; B-Lymphocytes; Binding; Biochemical; CD4 Positive T Lymphocytes; Cell physiology; Complex; Cytoplasmic Tail; Data; Development; Endocytosis; Fluorescence Resonance Energy Transfer; Goals; Helper-Inducer T-Lymphocyte; Histocompatibility Antigens Class II; Immune response; In Situ; Investigation; KAI1 gene; Laboratories; Laboratory Finding; Liquid substance; MHC Class II Genes; Mediating; Membrane; Membrane Microdomains; Microscopy; Molecular; Pathway interactions; Peptide Hydrolases; Peptide/MHC Complex; Peptides; Phase; Process; Production; Property; Proteins; Protocols documentation; Receptors, Antigen, B-Cell; Signal Transduction; Source; Specificity; Testing; Therapeutic; Time; Ubiquitination; antigen binding; antigen processing; design; inhibitor/antagonist; novel vaccines; receptor mediated endocytosis; uptake

DESCRIPTION (provided by applicant): Interactions between B cells and CD4 T cells are mediated by peptide-MHC class II complexes and support full development of a humoral immune response. B cells are antigen-specific antigen presenting cells, where immunologically relevant antigen processing occurs subsequent to B cell receptor (BCR)-mediated binding and internalization of cognate antigen. This laboratory has established that BCR-mediated antigen processing occurs subsequent to antigen (Ag)-BCR ubiquitination and results in expression of derivative peptide-class II complexes (termed "Type I" complexes) with unique functional and biochemical properties. The underlying hypothesis driving this project is that processing of Ag-BCR complexes occurs within an MHC class II peptide-loading complex (PLC) located in MHC class II enriched antigen processing compartments. To test this hypothesis, we will extend our new preliminary data and take a biochemical approach to further define the molecular composition of the class II PLC in B cells processing antigen internalized either via BCR-mediated or fluid-phase endocytosis (Aim 1). We will also utilize a "FRET microscopy" approach to study the dynamics of class II PLC formation in intact B cells (Aim 2). The overall goal of this proposal is to gain a better understanding of the molecular mechanism of class II peptide loading subsequent to BCR-mediated antigen processing, and to determine if class II peptide loading occurs within a PLC containing a dedicated source of antigenic peptide (i.e., Ag-BCR complexes). PUBLIC HEALTH RELEVANCE: Interactions between antigen specific B cells and CD4 helper T cells are restricted by B cell expressed peptide-MHC class II complexes. The goal of this project is to define the molecular mechanism by which antigen specific B cells generate these critical peptide-class II complexes. This information will be helpful in the design of new vaccines that enhance the production of these complexes or therapeutic protocols to dampen this mechanism in cases of autoimmunity.

描述（由申请人提供）：B 细胞和 CD4 T 细胞之间的相互作用由肽-MHC II 类复合物介导，并支持体液免疫反应的全面发展。 B 细胞是抗原特异性抗原呈递细胞，其中在 B 细胞受体 (BCR) 介导的同源抗原结合和内化之后发生免疫相关的抗原加工。该实验室已确定，BCR 介导的抗原加工发生在抗原 (Ag)-BCR 泛素化之后，并导致具有独特功能和生化特性的衍生肽 II 类复合物（称为“I 型”复合物）的表达。推动该项目的基本假设是 Ag-BCR 复合物的加工发生在位于 MHC II 类富集抗原加工区室中的 MHC II 类肽负载复合物 (PLC) 内。为了检验这一假设，我们将扩展新的初步数据，并采用生化方法进一步定义 B 细胞中通过 BCR 介导或液相内吞作用内化抗原的 II 类 PLC 的分子组成（目标 1）。我们还将利用“FRET 显微镜”方法来研究完整 B 细胞中 II 类 PLC 形成的动态（目标 2）。本次活动的总体目标 该提案的目的是更好地了解 BCR 介导的抗原加工后 II 类肽加载的分子机制，并确定 II 类肽加载是否发生在含有专用抗原肽源（即 Ag-BCR 复合物）的 PLC 内。 ）。 公共卫生相关性：抗原特异性 B 细胞和 CD4 辅助 T 细胞之间的相互作用受到 B 细胞表达的肽-MHC II 类复合物的限制。该项目的目标是确定抗原特异性 B 细胞生成这些关键肽 II 类复合物的分子机制。这些信息将有助于新疫苗的设计 增强这些复合物的产生或治疗方案，以在自身免疫的情况下抑制这种机制。