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细胞与CD4 T细胞之间的相互作用是由肽-MHC II类配合物介导的，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，在B细胞受体（BCR）介导的同源抗原的结合和内在化之后，发生免疫学相关的抗原加工。该实验室已经确定，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级II配合物（称为“ I型”配合物（称为“ I型”配合物）。驱动该项目的基本假设是，在MHC II富集富含抗原抗原加工室的MHC II类肽加载络合物（PLC）中，Ag-BCR复合物的处理发生。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II类PLC的分子组成在B细胞处理抗原通过BCR介导的或流体相位的内吞作用中内化的抗原中的分子组成（AIM 1）。我们还将利用一种“ FRET显微镜”方法研究完整B细胞中II类PLC形成的动力学（AIM 2）。总体目标 提案是为了更好地理解BCR介导的抗原加工后II类肽载荷的分子机制，并确定II类肽负荷是否发生在包含专门的抗原肽（即AG-BCR复合物）的PLC中。 公共卫生相关性：抗原特异性B细胞与CD4辅助T细胞之间的相互作用受B细胞表达的肽-MHC II类复合物的限制。该项目的目的是定义抗原特异性B细胞产生这些关键肽级II配合物的分子机制。此信息将有助于设计新疫苗 这可以增强这些复合物或治疗方案的产生，以抑制自身免疫性的情况。