Class II MHC Antigen Processing in Dendritic Cells

描述(申请人提供)：拟议研究的广泛的、长期的目标是表征树突状细胞(DC)中的抗原处理和递呈途径，以及这些途径如何与它们在启动和调节免疫反应中的功能相关。这项拟议的研究旨在确定多肽和蛋白质衍生的抗原在DC中被加载到II类MHC蛋白上的位置，以及树突状细胞成熟如何调节这一位置；确定未成熟DC中缺乏空的II类MHC蛋白的分子基础；评估空的II类MHC分子可能的功能作用；以及确定无肽的开放构象的结构特征。这些目标将通过细胞和生化分析来跟踪不同发育状态的抗原提呈细胞中II类MHC蛋白的占有率和肽结合活性，并使用细胞和免疫学分析来跟踪抗原提呈的功能结果。为此目的，研制了一种新型的多肽结合荧光探针。 项目简介：树突状细胞的抗原提呈在免疫系统识别和响应病原体的过程中发挥着关键作用。对负责抗原呈递的基本细胞过程的详细了解对于指导治疗方法以调节自身免疫和过敏等不适当的免疫反应、努力开发新的疫苗和改进现有的针对感染性病原体和癌症的疫苗将是重要的。

DESCRIPTION (provided by applicant): The broad, long-term objective of the proposed research is to characterize antigen processing and presentation pathways in dendritic cells (DC), and how these relate to their function in initiating and regulating immune responses. The proposed research is intended to determine the location within DC where peptide and protein-derived antigens are loaded onto class II MHC proteins, and how this is regulated by dendritic cell maturation; to determine the molecular basis for the lack of loading of empty class II MHC proteins present in immature DC; to evaluate possible functional roles for empty class II MHC molecules; and to determine structural characteristics of the peptide-free open conformation of HLA-DR1. These goals will be achieved using cellular and biochemical assays to follow the occupancy and peptide binding activity of class II MHC proteins in antigen presenting cells in different developmental states, and using cellular and immunological assays to follow the functional outcomes of antigen presentation. A novel fluorometric probe of peptide binding has been developed for this purpose. PROJECT NARRATIVE: Antigen presentation by dendritic cells plays a key role in the process by which the immune system recognizes and responds to pathogens. A detailed understanding of the basic cellular processes responsible for antigen presentation will be important to guide therapeutic approaches to regulating inappropriate immune responses as in autoimmunity and allergy, and for efforts to develop new vaccines and to improve existing vaccines against infectious agents and cancer.